The 11th Annual Meeting of the IHMF

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The 11th Annual Meeting of the IHMF
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KSHV/HHV8-related Cancer
Chris BoshoffProfessor of Cancer Medicine
University College LondonU.K.
Pictures Cape Town
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CANCER VIRUS Kaposis sarcoma (KS) KSHV Non HD
Lymphoma (NHL) EBV KSHV Hodgkins
Disease EBV Anogenital Cancers HPV Skin
Cancers HPV Liver Cancers HCV, HBV
The Washington Post
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NY State AIDS Cancer Incidence (1981-1994)
Kaposis sarcoma 97.5 Non HD lymphoma 37.4 Liver
primary 5.1 Skin, non-KS 20.9 Hodgkins disease
8.0 Melanoma 1.4 Rectum and anus 3.3 Cervix 9.1
Colon 0.8 Breast 0.8 Prostate 0.7 Ovary 0.8
Am J Epid 2001, 154 544-556
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From Friedman-Kien
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KSHV

• Kaposis sarcoma-associated herpesvirus
• Human herpesvirus-8
• Rhadinovirus
• dsDNA genome
• 140kb

EM from D Ablashi
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From A Gessain
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KSHV Seroprevalence, South Africa
Age Group
3440 sera, blood donors patients with cancer
NEJM, 1999,3401863
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South Africa
Type of Site of Cancer (no. of patients)
Presence of Any Positive Signal
Presence of High-Intensity Signal
Oral cavity (86)
Esophagus (306)
Stomach (51)
Colon or rectum (103)
Liver (88)
Lung (117)
Kaposis sarcoma (51)
Breast (415)
Cervix (711)
Ovary (64)
Prostate (202)
Other genital (132)
Hodgkins disease (121)
Non-Hodgkins lymphoma (122)
Multiple myeloma (108)
Leukemia (280)
Other cancers (387)
Blood donors (85)
0
20
40
60
80
100
0
20
40
60
80
100
Standardized Prevalence ()
Standardized Prevalence ()
NEJM, 1999
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SOUTH AFRICAMOTHER-TO-CHILD TRANSMISSION
MOTHER STATUS 0-4
5-9 10-14 All KSHV
seropositive 29 29 80
42 KSHV seronegative 0 0
13 1
Age of children, years
NEJM 1999, 3411241
13
70
C
60
50
40
Percentage positive
30
20
10
0
UK
US
INDIA
ITALY
CUBA
CHINA
SPAIN
BRAZIL
JAPAN
ISRAEL
GHANA
ZAMBIA
GAMBIA
TRINIDAD
JAMAICA
GREECE
ALBANIA
UGANDA
THAILAND
HUNGURY
GERMANY
SRI LANKA
MALAYSIA
GREENLAND
SOUTH AFRICA
SIERRA LEONE
FRENCH GUIANA
Bourboulia, 2004
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PATCH - lt10 spindle cells KSHV
PNAS 1999, 964546-4551
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Lytic infection in Kaposi
Said et al, J Pathol 1997, 182273
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Role of lytic infection

• Electron microscopy
• Increased viral load predicts development of
  KS(Lancet 1996 Whitby et al)
• Anti-herpesviral agents (ganciclovir and
  cidofovir) might prevent KS development (Martin
  et al, NEJM 1999)
• KSHV episome unstable (Ganem, JCI, 2004)

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A
K1
K15
CBP
ssDBP
T R
vOx-2
vGPCR
gB
LANA-
DNA Pol
4
6
75
vCyclin
7
74
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vIL-6
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K14
vFLIP
73
10
DHFR
11
72
TS
K2
71
Kaposins
K3
vMIP-II
DR2
70
K12
K4
DR1
vMIP-III
69
K4.1
68
K4.2
vMIP-I
K5
65-67
K6
Tegument proteins
vBcl-2
K7
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17
18
64
Tegument protein
KSHV Episome 140kb
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105kb
35kb
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63
21
TK
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gH
22
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Ribonucleotide reductase
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60
24
59
25
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Major capsid protein
DNA replication protein
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K11
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K10.1
29b
Minor capsid protein
K10
30-33
vIRFs ?
K9
29a
34-38
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Packaging Proteins
K8.1
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vIRF -1
39
55
54
40
K8
Kinase
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53
43
45-47
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52
44
50
49
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DNA replication protein
Alkaline exonuclease
gM
Rta-like
UDG
Helicase-primase
ZEBRA-like
70kb
From Sharp Boshoff Life, 2000
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Oncogenic viral proteins
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vGPCR
vCD200
LANA
vCyclin
vFLIP
Super cyclin Cell cycle Interfere with
Apoptosis
Interfere with pRb, p53, ?-catenin pathways
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Cellular origin of Kaposis sarcoma
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All KS spindle cells VEGFR3
PNAS 1999, 964546 (Dupin et al)
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Cross et al, 2003 TiBS
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Kaposi Treatment
Treatment
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Pulmonary KS
DURING HAART
BEFORE HAART
From Nick Dupin, Paris
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What happens to anti-KSHV immune responses during
HAART?
Peptide response
KSHV Ab response
1000
106
105
800
CD8
104
600
103
CD4
400
HIV-1 viral load
102
200
101
KSHV viral load
0
1
0
6
2
3
4
5
1
0
6
2
3
4
5
1
Months on therapy
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(a) Kaposis sarcoma
10 9 8 7 6 5 4 3 2 1 0
Rate per 1000 Person-years
Calendar period of diagnosis
(b) Non-Hodgkins lymphoma
5
4
Rate per 1000 Person-years
3
2
1
0
Calendar period of diagnosis
Need international update of different HAART
combinations
Need to understand mechanisms
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Conclusions

• Global seroprevalence of KSHV correlates with
  risk of KS
• Lytic and latent infection (viral proteins) play
  a role
• KSHV cyclin, FLIP and LANA involved in
  oncogenesis
• KSHV induces a network of cytokines after
  infection of EC
• Anti-KSHV immune restoration occur during HAART

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HELSINKI Kari Alitalo UCL Mary Collins Robin
Weiss IC Frances Gotch
UNIVERSITY COLLEGE LONDON
Kaposi Treatment
WOLFSON INSTITUTE FOR BIOMEDICAL
RESEACH Dimitra Bourboulia Dimitrios
Lagos Tyson Sharp Stephen Henderson Heike
Laman Mark Cannon Sham Direkze Andrew
Godfrey Andrew Koumi Nando Munoz Juan
Funes Matthew Trotter Nigel Field Mali
Weisz Hsei-Wei Wang
Cancer Research U.K. MRC The Wellcome Trust LRF