NY State AIDS Cancer Incidence (1981-1994)

Kaposi’s sarcoma 97.5NHL 37.4Liver primary 5.1Skin, non-KS 20.9Hodgkin’s disease 8.0Melanoma 1.4 Rectum and Anus 3.3Cervix 9.1

Colon 0.8Breast 0.8Prostate 0.7Ovary 0.8

Am J Epid 2001, 154: 544-556

EBV

HVSKSHV/HHV-8

VZV

HSV-1

HSV-2

HHV-6

HCMV

HHV-7

Herpesvirus taxonomy

Detection of KSHV in Kaposi's Sarcoma

Biopsy PCR SerologyLANA + K8.1

Tumour No. Tested

% +ve No. Tested

% +ve

AIDS-KS 259 97 259 86

Classic KS 169 94 169 100

Transplant KS 13 100 40 100

African KS 75 93 175 98

Controls 15

(skin)

0 743

(UK)

2.8

Whitby et al., JNCI, 1999

Mother’s KSHV

antibody titer

Percentage of children

seropositive for KSHV

Negative (<1:100) 1%

1:200 to 1:1,600 33%

1:3,200 to 1:12,800 43%

1:25,600 or greater 50%

NEJM 1999, 341:1241

Age of children, yearsMOTHER STATUS 0-4 5-9 10-14 All

KSHV seropositive 29% 29% 80% 42%

KSHV seronegative 0% 0% 13% 1%

SOUTH AFRICAMOTHER-TO-CHILD TRANSMISSION

Bourboulia et al., JAMA 1998, 280: 31

Cellular Homologues in the KSHV Genome

Cellular proliferation v-Cyclin Dv-GPCRv-IRF

Apoptosis inhibitors v-bcl-2v-FLIPv-IL-6

Chemokines v-MIP1v-MIP2v-MIP3

>15% of the viral genes are pirates from the eukariotic cellular DNA

AIDS-associated lymphoproliferations

EBV orEBV +KSHV

EBV

KSHVKSHV

Naïve B-cellNaïve B-cell

Memory B-cellMemory B-cell

BLBL(EBV) (EBV)

MCD MCD (KSHV)(KSHV)

PELPEL(KSHV + EBV)(KSHV + EBV)

Plasma cellPlasma cell

Germinal CentreGerminal Centre

PEL PEL (KSHV)(KSHV)

GLDGLD(KSHV + EBV)(KSHV + EBV)

PERIPHERY

TONSIL

EBNA2+, LMP1, 2+

EBNA-1+

LANA1+vIL-6+vIRF1+

LANA1+vIL6+

Reasons for Response of KS to ART

ACTION MECHANISM

KSHV immune reconstitution KSHV CTLs target and kill KSHV infected spindle Restoration of cellular immune response cells

Reduction of HIV-1 Tat and other Cytokines involved in the stimulation of KSinflammatory cytokine levels angiogenesis (eg. bFGF)

Protease inhibitor (PI) based regimens PI has been shown to block KS spindle cell growthhave a direct anti-spindle cells and and KS-induced angiogenesis in experimentalanti-angiogenic effect models