Transcript presentation

NY State AIDS Cancer Incidence (1981-1994)
Kaposi’s sarcoma
NHL
Liver primary
Skin, non-KS
Hodgkin’s disease
Melanoma
Rectum and Anus
Cervix
Colon
Breast
Prostate
Ovary
97.5
37.4
5.1
20.9
8.0
1.4
3.3
9.1
0.8
0.8
0.7
0.8
Am J Epid 2001, 154: 544-556
Herpesvirus taxonomy
HVS
KSHV/HHV-8

EBV
HSV-1
HSV-2

HHV-7

HHV-6
HCMV
VZV
Detection of KSHV in Kaposi's Sarcoma
Biopsy PCR
Tumour
No.
Tested
AIDS-KS
259
97
259
86
Classic KS
169
94
169
100
Transplant KS
13
100
40
100
African KS
75
93
175
98
15
(skin)
0
743
(UK)
Controls
% +ve
Serology
LANA + K8.1
No.
Tested
% +ve
2.8
Whitby et al., JNCI, 1999
SOUTH AFRICA
MOTHER-TO-CHILD TRANSMISSION
MOTHER STATUS
Age of children, years
0-4
5-9
10-14
All
KSHV seropositive
29%
29%
80%
42%
KSHV seronegative
0%
0%
13%
1%
Bourboulia et al., JAMA 1998, 280: 31
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
Cellular Homologues in the
KSHV Genome
Cellular proliferation
v-Cyclin D
v-GPCR
v-IRF
Apoptosis inhibitors
v-bcl-2
v-FLIP
v-IL-6
Chemokines
v-MIP1
v-MIP2
v-MIP3
>15% of the viral genes are pirates from the
eukariotic cellular DNA
AIDS-associated
lymphoproliferations
Naïve B-cell
PERIPHERY
KSHV
TONSIL
KSHV
EBV or
EBV +KSHV
EBNA-1+
Memory B-cell
LANA1+
vIL-6+
vIRF1+
MCD
(KSHV)
EBV
GLD
(KSHV + EBV)
BL
(EBV)
EBNA2+,
LMP1, 2+
Germinal Centre
LANA1+
vIL6+
PEL
(KSHV)
PEL
(KSHV + EBV)
Plasma cell
Reasons for Response of KS to ART
ACTION
MECHANISM
KSHV immune reconstitution
Restoration of cellular immune response
KSHV CTLs target and kill KSHV infected spindle
cells
Reduction of HIV-1 Tat and other
inflammatory cytokine levels
Cytokines involved in the stimulation of KS
angiogenesis (eg. bFGF)
Protease inhibitor (PI) based regimens
have a direct anti-spindle cells and
anti-angiogenic effect
PI has been shown to block KS spindle cell growth
and KS-induced angiogenesis in experimental
models