Congenital and acquire

Immunodeficiency

Wei Chen Associate professorInstitute of Immunology

E-mailchenwei566zjueducnhttpmypagezjueducn566 8888

Objectives

1048698 To understand the concept of immunodeficiency

To know the main types of primary immunodeficiency diseases

1048698 Be able to describe characteristics and consequence of HIV infection

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Immunodeficiency

Defects in the development and functions of the immune system

Result in increased susceptibility to infections and in an increased incidence of certain cancers

Disorders caused by defective immunity are called immunodeficiency diseases

General feature of immunodeficiency diseases

The principal consequence of immunodeficiency is an increased susceptibility to infection

Patients with immunodeficiencies are also susceptible to certain types of cancer

Paradoxically certain immunodeficiencies are associated with an increased incidence of autoimmunity

Immunodeficiency may result from defects in lymphocyte development or activation or from defects in the effector mechanisms of innate and adaptive immunity

Classification Primary or congenital immunodeficiencies

Present at birthResult from genetic abnormalities in one or more components of the immune system

Secondary or acquired immunodeficienciesLater in lifeResult from infections malnutrition or treatments that cause loss or inadequate function of various components of the immune systemMost common is acquired immunodeficiency syndrome or AIDS

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Primary immunodeficiency diseases

Severe Combined Immunodeficiencies (SCID)

Antibody Deficiencies Defects in B Cell

Development and Activation

Defects in T Lymphocyte Activation and

Function

Defects in Innate Immunity

Multisystem Disorders with immunodeficiency

Features of immunodeficiency diseases

congenital immunodeficiencies caused by defects in lymphocyte maturation

Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies

characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help

Children with SCID usually have infections during the first year of life

Severe Combined Immunodeficiency Syndromes

(SCID)

Severe Combined Immunodeficiency Syndromes

(SCID)

Athymic - DiGeorge Syndrome

X-linked SCID (c deficiency)

Adenosine deaminase deficiency ( 腺苷脱氨酶 )

Jak3 kinase deficiency

Purine nucleoside phosphorylase deficiency

Bare lymphocyte syndrome

RAG1 and RAG2 deficiency

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Immunodeficiency

Defects in the development and functions of the immune system

Result in increased susceptibility to infections and in an increased incidence of certain cancers

Disorders caused by defective immunity are called immunodeficiency diseases

General feature of immunodeficiency diseases

The principal consequence of immunodeficiency is an increased susceptibility to infection

Patients with immunodeficiencies are also susceptible to certain types of cancer

Paradoxically certain immunodeficiencies are associated with an increased incidence of autoimmunity

Immunodeficiency may result from defects in lymphocyte development or activation or from defects in the effector mechanisms of innate and adaptive immunity

Classification Primary or congenital immunodeficiencies

Present at birthResult from genetic abnormalities in one or more components of the immune system

Secondary or acquired immunodeficienciesLater in lifeResult from infections malnutrition or treatments that cause loss or inadequate function of various components of the immune systemMost common is acquired immunodeficiency syndrome or AIDS

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Primary immunodeficiency diseases

Severe Combined Immunodeficiencies (SCID)

Antibody Deficiencies Defects in B Cell

Development and Activation

Defects in T Lymphocyte Activation and

Function

Defects in Innate Immunity

Multisystem Disorders with immunodeficiency

Features of immunodeficiency diseases

congenital immunodeficiencies caused by defects in lymphocyte maturation

Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies

characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help

Children with SCID usually have infections during the first year of life

Severe Combined Immunodeficiency Syndromes

(SCID)

Severe Combined Immunodeficiency Syndromes

(SCID)

Athymic - DiGeorge Syndrome

X-linked SCID (c deficiency)

Adenosine deaminase deficiency ( 腺苷脱氨酶 )

Jak3 kinase deficiency

Purine nucleoside phosphorylase deficiency

Bare lymphocyte syndrome

RAG1 and RAG2 deficiency

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Immunodeficiency

Defects in the development and functions of the immune system

Result in increased susceptibility to infections and in an increased incidence of certain cancers

Disorders caused by defective immunity are called immunodeficiency diseases

General feature of immunodeficiency diseases

The principal consequence of immunodeficiency is an increased susceptibility to infection

Patients with immunodeficiencies are also susceptible to certain types of cancer

Paradoxically certain immunodeficiencies are associated with an increased incidence of autoimmunity

Immunodeficiency may result from defects in lymphocyte development or activation or from defects in the effector mechanisms of innate and adaptive immunity

Classification Primary or congenital immunodeficiencies

Present at birthResult from genetic abnormalities in one or more components of the immune system

Secondary or acquired immunodeficienciesLater in lifeResult from infections malnutrition or treatments that cause loss or inadequate function of various components of the immune systemMost common is acquired immunodeficiency syndrome or AIDS

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Primary immunodeficiency diseases

Severe Combined Immunodeficiencies (SCID)

Antibody Deficiencies Defects in B Cell

Development and Activation

Defects in T Lymphocyte Activation and

Function

Defects in Innate Immunity

Multisystem Disorders with immunodeficiency

Features of immunodeficiency diseases

congenital immunodeficiencies caused by defects in lymphocyte maturation

Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies

characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help

Children with SCID usually have infections during the first year of life

Severe Combined Immunodeficiency Syndromes

(SCID)

Severe Combined Immunodeficiency Syndromes

(SCID)

Athymic - DiGeorge Syndrome

X-linked SCID (c deficiency)

Adenosine deaminase deficiency ( 腺苷脱氨酶 )

Jak3 kinase deficiency

Purine nucleoside phosphorylase deficiency

Bare lymphocyte syndrome

RAG1 and RAG2 deficiency

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

General feature of immunodeficiency diseases

The principal consequence of immunodeficiency is an increased susceptibility to infection

Patients with immunodeficiencies are also susceptible to certain types of cancer

Paradoxically certain immunodeficiencies are associated with an increased incidence of autoimmunity

Immunodeficiency may result from defects in lymphocyte development or activation or from defects in the effector mechanisms of innate and adaptive immunity

Classification Primary or congenital immunodeficiencies

Present at birthResult from genetic abnormalities in one or more components of the immune system

Secondary or acquired immunodeficienciesLater in lifeResult from infections malnutrition or treatments that cause loss or inadequate function of various components of the immune systemMost common is acquired immunodeficiency syndrome or AIDS

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Primary immunodeficiency diseases

Severe Combined Immunodeficiencies (SCID)

Antibody Deficiencies Defects in B Cell

Development and Activation

Defects in T Lymphocyte Activation and

Function

Defects in Innate Immunity

Multisystem Disorders with immunodeficiency

Features of immunodeficiency diseases

congenital immunodeficiencies caused by defects in lymphocyte maturation

Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies

characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help

Children with SCID usually have infections during the first year of life

Severe Combined Immunodeficiency Syndromes

(SCID)

Severe Combined Immunodeficiency Syndromes

(SCID)

Athymic - DiGeorge Syndrome

X-linked SCID (c deficiency)

Adenosine deaminase deficiency ( 腺苷脱氨酶 )

Jak3 kinase deficiency

Purine nucleoside phosphorylase deficiency

Bare lymphocyte syndrome

RAG1 and RAG2 deficiency

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Classification Primary or congenital immunodeficiencies

Present at birthResult from genetic abnormalities in one or more components of the immune system

Secondary or acquired immunodeficienciesLater in lifeResult from infections malnutrition or treatments that cause loss or inadequate function of various components of the immune systemMost common is acquired immunodeficiency syndrome or AIDS

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Primary immunodeficiency diseases

Severe Combined Immunodeficiencies (SCID)

Antibody Deficiencies Defects in B Cell

Development and Activation

Defects in T Lymphocyte Activation and

Function

Defects in Innate Immunity

Multisystem Disorders with immunodeficiency

Features of immunodeficiency diseases

congenital immunodeficiencies caused by defects in lymphocyte maturation

Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies

characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help

Children with SCID usually have infections during the first year of life

Severe Combined Immunodeficiency Syndromes

(SCID)

Severe Combined Immunodeficiency Syndromes

(SCID)

Athymic - DiGeorge Syndrome

X-linked SCID (c deficiency)

Adenosine deaminase deficiency ( 腺苷脱氨酶 )

Jak3 kinase deficiency

Purine nucleoside phosphorylase deficiency

Bare lymphocyte syndrome

RAG1 and RAG2 deficiency

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Primary immunodeficiency diseases

Severe Combined Immunodeficiencies (SCID)

Antibody Deficiencies Defects in B Cell

Development and Activation

Defects in T Lymphocyte Activation and

Function

Defects in Innate Immunity

Multisystem Disorders with immunodeficiency

Features of immunodeficiency diseases

congenital immunodeficiencies caused by defects in lymphocyte maturation

Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies

characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help

Children with SCID usually have infections during the first year of life

Severe Combined Immunodeficiency Syndromes

(SCID)

Severe Combined Immunodeficiency Syndromes

(SCID)

Athymic - DiGeorge Syndrome

X-linked SCID (c deficiency)

Adenosine deaminase deficiency ( 腺苷脱氨酶 )

Jak3 kinase deficiency

Purine nucleoside phosphorylase deficiency

Bare lymphocyte syndrome

RAG1 and RAG2 deficiency

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Primary immunodeficiency diseases

Severe Combined Immunodeficiencies (SCID)

Antibody Deficiencies Defects in B Cell

Development and Activation

Defects in T Lymphocyte Activation and

Function

Defects in Innate Immunity

Multisystem Disorders with immunodeficiency

Features of immunodeficiency diseases

congenital immunodeficiencies caused by defects in lymphocyte maturation

Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies

characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help

Children with SCID usually have infections during the first year of life

Severe Combined Immunodeficiency Syndromes

(SCID)

Severe Combined Immunodeficiency Syndromes

(SCID)

Athymic - DiGeorge Syndrome

X-linked SCID (c deficiency)

Adenosine deaminase deficiency ( 腺苷脱氨酶 )

Jak3 kinase deficiency

Purine nucleoside phosphorylase deficiency

Bare lymphocyte syndrome

RAG1 and RAG2 deficiency

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Features of immunodeficiency diseases

congenital immunodeficiencies caused by defects in lymphocyte maturation

Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies

characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help

Children with SCID usually have infections during the first year of life

Severe Combined Immunodeficiency Syndromes

(SCID)

Severe Combined Immunodeficiency Syndromes

(SCID)

Athymic - DiGeorge Syndrome

X-linked SCID (c deficiency)

Adenosine deaminase deficiency ( 腺苷脱氨酶 )

Jak3 kinase deficiency

Purine nucleoside phosphorylase deficiency

Bare lymphocyte syndrome

RAG1 and RAG2 deficiency

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

congenital immunodeficiencies caused by defects in lymphocyte maturation

Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies

characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help

Children with SCID usually have infections during the first year of life

Severe Combined Immunodeficiency Syndromes

(SCID)

Severe Combined Immunodeficiency Syndromes

(SCID)

Athymic - DiGeorge Syndrome

X-linked SCID (c deficiency)

Adenosine deaminase deficiency ( 腺苷脱氨酶 )

Jak3 kinase deficiency

Purine nucleoside phosphorylase deficiency

Bare lymphocyte syndrome

RAG1 and RAG2 deficiency

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies

characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help

Children with SCID usually have infections during the first year of life

Severe Combined Immunodeficiency Syndromes

(SCID)

Severe Combined Immunodeficiency Syndromes

(SCID)

Athymic - DiGeorge Syndrome

X-linked SCID (c deficiency)

Adenosine deaminase deficiency ( 腺苷脱氨酶 )

Jak3 kinase deficiency

Purine nucleoside phosphorylase deficiency

Bare lymphocyte syndrome

RAG1 and RAG2 deficiency

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Severe Combined Immunodeficiency Syndromes

(SCID)

Athymic - DiGeorge Syndrome

X-linked SCID (c deficiency)

Adenosine deaminase deficiency ( 腺苷脱氨酶 )

Jak3 kinase deficiency

Purine nucleoside phosphorylase deficiency

Bare lymphocyte syndrome

RAG1 and RAG2 deficiency

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Precursor T cell differentiation defect

Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

DiGeorge syndrome

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency

Most common form of SCID (40)

Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15

Very low T cells and NK cells with low to normal numbers of B cells

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Nude Athymic mouse

FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Antibody Deficiencies Defects in B Cell Development and

Activation

Brutonrsquos (X-linked) Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Autosomal Recessive Hyper-IgM Syndrome

B Cell Receptor Deficiencies

Selective IgA Deficiency

IgG Subclass Deficiency

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

XLA - BTK defect

Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Essential role of BTK

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Brutonrsquos X-linked Agammaglobulinemia

The absence of B cells in blood and IgG

x-linked recessive inheritance males

Child clinically well for first 6 months of life

Recurrent upperlower respiratory tract infections with encapsulated bacteria

Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections

Paucity of lymphoid tissue (tonsils adenoids)

Treatment inject pooled gamma globulin preparations

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Common Variable Immunodeficiency

Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly

Absence of clear abnormalities in T and B cell subsets

Chronicrecurrent respiratory infections diarrhea(腹泻 )

Tendency to develop autoimmunity and lymphoid malignancies

Linkage to HLA Class III Region in 23 of patients

One gene identified ICOS (B7h) (activation antigen on T cells)

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Defects in Innate Immunity

Phagocyte Deficiencies

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency (LAD I)

Complement Deficiency

Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome

Inherited defects in TLR Pathways NF-κB signaling and type I Interferons

IL-12IFN pathway deficiencies

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Congenital immunodeficiencies caused by defects in innate immunity

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Chronic Granulomatous Disease

Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase

Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Chronic granulomatous disease

Note cervical nodal abscess(头颈淋巴结脓肿 )

Gingivitis and periodontitis (牙龈炎和牙周炎 )

Abscess indenting the oesophagus(食道脓肿 )

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

CGD patient with

skin infections

due to Serratia

marcescens

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Content

Introduction

Primary immunodeficiency diseases

Secondary immunodeficiency

diseases

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Secondary or acquired immunodeficiency diseases

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Human Immunodeficiency Virus

Discovered in 1983 by Luc Montagnier and Robert Gallo

Retrovirus (RNA virus)

HIV-1 (common) and HIV-2 (Africa)

Patients with low CD4+ T cells

Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers

Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc

Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Kaposi Sarcoma

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Incidence of HIV

CDC 2008

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

HIV - The Virus

A retrovirus

Genetic material is RNA

Transcribed into DNA by RT (reverse transcriptase)

Copy (provirus) inserted into the host genome

When it is expressed to form new virions the cell lyses

Alternately it may remain latent in the cell for an extended period of time

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

The structure of human HIV-1

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Genes of human HIV-1

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

The life cycle of HIV-1

Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M

Production of viral DNA and its integration into the host genome

Expression of viral genes production of viral RNAs and then proteins to form a core structure

Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

The life cycle of HIV-1

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Pathogenesis of AIDS

HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS

The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Course of AIDS

ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)

Anti-HIV AbCTL

Dissemination of virus Seeding of lymphoid organs

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

The pathogenesis of AIDS

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

The earliest innate and adaptive immune responses detected after HIV

transmission

Nat Rev Immunol 20101011

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Animal Models

Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)

Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

US Death Rates

25-44 years old

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Therapy and vaccination strategies

Several places in virus life-cycle that can be blocked

Attachmententry

Reverse transcription

Integration

Proteolysis

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Reverse Transcription

AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop

NevirapineInhibits action of RT

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Protease Inhibitors

Blocks action of protease

Huge breakthrough

Responsible for rapid drop in number of deaths in US

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Combination Therapy

HAART is a combination therapy

Highly Active Anti-Retroviral Therapy

Two nucleoside analogs and one protease inhibitor

Helps to prevent rapid mutating viruses from developing resistance

Can reduce virus to undetectable levels

Expensive ($15000yr)

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Therapies

Ongoing work to develop drugs to interfere with integration and with attachmententry

Takes many years to pass tests for safety and efficacy

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect

Vaccines

Has been much harder to develop a vaccine for HIV than it has been for other viruses

Results have been disappointing

Can get antibodies but they donrsquot protect