Immunology of HIV
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Transcript of Immunology of HIV
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Immunology of HIV
Rupert Kaul
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“The immunology of HIV”
1. Review of HIV-1, life cycle, transmission2. How does HIV infect a person?
• Mucosal immune events
3. How does HIV cause disease?• Direct vs bystander, gut events
4. How does the host fight back?• Implications for vaccines, therapeutics
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HIV structure
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HIV - virus, genetics• HIV is a lentivirus - an RNA virus from the class
of retroviruses• 2 HIV species (1 and 2) - 40-50% homologous• Several HIV clades - A,B,C,D,A/E,O (others) -
70-80% homologous• Within a clade - 85-90% homologous• Within an individual - “quasispecies” >95%
homologous• About 109 viruses produced per day, error-prone
reverse transcriptase (q 10-4-10-5)
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(1) HIV-1 attachment; (2) Fusion; (3) Cell entry; (4) Reverse transcription, formation of the pre-integration complex (PIC); (5) Nuclear transport; (6) Chromosomal integration of DNA provirus; (7) Transcription of viral RNA; (8) Nuclear export of RNA; (9) Translation and processing; (10) Membrane transport; (11) Virion assembly; (12) Budding; (13) Maturation.
HIV-1 life cycle
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HIV - clinical progression
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Two contrasting facts:
HIV has spread widely and rapidly…
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UK PEP Guidelines, 2006.
…and yet HIV is relatively difficult to transmit
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Blood viral load correlates with transmission.
Quinn, T.2000.
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Blood HIV levels predict amount of virus in “genital fluids”
Sheth P; J Immunol, 2005. Kovacs A; Lancet, 2001.
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Genital/mucosal protective factors
• Genital tract repels >99% of HIV exposures• Combination of factors:
– Intact epithelium– Mucus, pH, SLPI, lactoferrin, Trappin-2, etc– ?Adaptive mucosal immunity
• Lack of co-infections also important
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Hladik F. Immunity, 2007.
Haase A. Nat Imm Rev, 2005.
What are the major genital HIV targets?
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Penile HIV target cells
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Mucosal immune protection vs HIV…
Viewpoint.Coates T, et al. Lancet, 2007.
• 3 large RCTs in SSA showed clear benefit• Very consistent results in Uganda, Kenya, SA• Efficacy: ITT ~55%, OTA ~63%• In Kenya: incidence 2.1% vs 4.2% • No short term behavioural disinhibition
– is being followed prospectively
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Mucosal immunology and coinfections
Freeman E, AIDS, 2006;
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Cervical target cells in HIV(-) women
• These associations were seen in HSV-2 infected women in the absence of HSV-2 DNA shedding or clinically apparent ulceration
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How does HIV cause disease?
• Not direct depletion of CD4+ T cells• See a number of immune effects that contribute:
– Increased immune activation– ? Via switched on innate immunity, ? damage to gut
mucosa– Leads to skewed T cell function, apoptosis
• Loss/dysfunction of many cell types:– pDCs, other dendritic cell subsets– CD4 and CD8 T cells– NK cells, NKT cells, GD cells, etc etc
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Mehandru et al. PLoS Med, 2006.
HIV: immune effects on the gut
Brenchley et al. JEM, 2004
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47 and HIV infection
Johnson P. NEJM, 2008.
Mora J.Nature, 2003.
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Gut events and HIV pathogenesis
Brenchley J. Nat Med, 2006.
HYPOTHESIS:• GI mucosal
immune defects bacterial translocation systemic immune activation CD4 depletion.
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Bacterial translocation andinflammation
Silvestri G. AIDS Rev, 2008.
• Systemic inflammation correlates closely with both:– Bacterial translocation– Rate of CD4 depletion
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Non-pathogenic SIV models:Sooties and AGMs
Silvestri G.Blood, 2008; Immunity, 2003
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Lessons from non-pathogenic models*
• Do not see enhanced cellular immunity• Do see reduced inflammation - initial
“blip”, rapidly downregulated• Do see CD4+ depletion in the gut, but
transient and then recovers• Target “shielding”??
– SM - reduced CCR5 expression if activated– AGM - “CD4(-)” T helpers not depleted
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Host defenses: antibodies
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HIV: antibody responses
• IgG response is ubiquitous - basis of diagnosis• Most people do make neutralizing Abs against
their own virus• BUT only work against the virus that was there a
few months ago - not the one that is there today• Failure of infused “cocktail” to impact infection
for more than a few days
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HIV antibody responses (2)
• Conformational masking - entropy• Lack of broad neutralization• Shielding of highly-conserved coreceptor binding
regions by hypervariable loops• “Irrelevant" antibodies vs gp120 monomers, or
non-critical regions of the gp120-trimer (debris)• Surface glycosylation: focused changes in glycan
packing prevent neutralizing Ab binding but not receptor binding
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Wei X.Nature, 2003.
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HIV antibody responses (3)
• BUT: some are specific for conserved regions, do neutralize primary virus, synergize – F105, b12 - CD4 binding site of gp120 – 2G12 - complex gp120 epitope– 2F5, 4E10, Z13 - gp41– OTHERS just described
• **Passive infusion of cocktail = ONLY model of sterilizing immunity (MCH, PEP trials)
• ?Pre-formed Ab applicable via microbicides
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Host defenses: CTL
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Sewell A2001
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CTL responses: any good?
• In primate models, vaccine-induced CTL can slow progression, improve viral control
• Timing of CTL and control • CD8+ depletion experiments• CTL (CD8+) impose major immune pressure on
virus (SIV, HIV)• HIV-specific CD4+, CD8+ responses found in
exposed, uninfected populations
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Immune time course post infection
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Kiepela et al. Nature, 2004
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CTL: not good enough…
1. Proviral latency - no antigen expressed2. Downregulation of HLA class I (nef, vpu)3. Upregulation of Fas ligand 4. Mutation:
• epitope mutation prevents HLA binding, TLR binding• flanking mutations prevent processing• BUT do see benefits from a “less fit” virus
5. Impaired CD8+ function
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Escape from CTL control
Mutation: Other:
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Ahmed R, et al. J Exp Med, 2006.
Cellular immune “exhaustion”
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HIV superinfection can occur
• Despite strong CTL, can be infected by a second strain of HIV-1
• But may be less common than initial infection
• ?? Half as likely to happen (very unclear)
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Real life HIV protection? exposed uninfected individuals
• People who “should be infected but aren’t”– sex workers, discordant couples, etc
• Several correlates:– Lack of CCR5– HIV specific cellular immunity: lysis, IFNg,
proliferation (generally low level)– HIV neutralizing IgA– Dampened immune activation
• ? Actually mediating protection vs. paraphenomenon
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Immune correlates of HIV protection: long-term nonprogressors
• People who “should be sick but aren’t”– Infected for >10 years, normal immune system, low VL– Also “elite controllers” - low/undetectable VL
• Several correlates:– Certain class I HLA types: B5701/03, B27, etc– HIV specific cellular immunity: breadth? Function?– No good humoral associations
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Polyfunctionality and survival
Betts, MBlood, 2006
Progressors
LTNP
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Vaccine-induced CTL: are they useful?
• Macaque models - several show that inducing SIV/SHIV-specific CD8+ T cells can lower viral load, slow/prevent progression
• Generally don’t prevent infection - but maybe could protect against “real” challenge?
• Hard to induce using candidate vaccines • Case of human infection post vaccine despite
strong CD8+ responses against dominant epitope
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STEP TRIAL
• Merck HIV vaccine• Adenovirus (Ad5) based, sole goal was to
induce cellular immunity• Did so fairly well, BUT…
– No protection against infection– No impact on post-infection VL– Increased HIV rates if prior adeno infection
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Summary
1. Resistance to acquisition is the norm2. Gut events / immune activation and disease3. Cellular responses are primarily responsible for
(inadequate) control post-infection4. Antibody responses against specific epitopes
may provide passive protection 5. Circumcision is an effective mucosal
intervention