© 1998 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 23, 51-54,
1998
© 1998 Oxford University Press
Human Herpesvirus Type 8 and Kaposi's Sarcoma
* Affiliation of authors: Institute of Cancer Research, Chester Beatty Laboratories, London, U.K.
Correspondence to: Robin A. Weiss, Ph.D., Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Rd., London SW3 6JB, U.K.
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Abstract |
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Kaposi's sarcoma-associated herpesvirus or human herpesvirus type 8 (HHV-8) is present in all forms of Kaposi's sarcoma (KS) as well as in primary effusion lymphomas and some cases of Castleman's disease. In KS tissues, HHV-8 is present in endothelial and spindle cells. Current serologic tests suggest that HHV-8 is predominantly found in those at risk of KS and is not as widespread as most other human herpesviruses. HHV-8 encodes various proteins that may play a role in promotion of cellular growth, including cyclin- and G-coupled protein receptor homologues, and anti-apoptotic proteins, including Bcl-2, IL-6 (i.e., interleukin 6), and FLIP (i.e., FLICE inhibitory protein) homologues. In addition, HHV-8 encodes two macrophage inflammatory-like proteins with anti-human immunodeficiency virus and angiogenic potential.
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Introduction |
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This conference is a timely opportunity to focus on the cancers that occur more frequently in acquired immunodeficiency syndrome (AIDS). Kaposi's sarcoma (KS) with Pneumocystis carinii infection heralded the AIDS epidemic in its earliest days. KS is seen frequently in Africa and is linked both to human immunodeficiency virus (HIV) (the epidemic form) and HIV-negative KS (the endemic form). It is also endemic in northern Mediterranean and eastern European countries. We shall focus on human herpesvirus type 8 (HHV-8)/Kaposi's sarcoma-associated herpesvirus (KSHV), but many more details are presented later in the conference when molecular biologists analyze the viral genome and describe how it replicates and functions.
The study of HHV-8/KSHV started less than 3 years ago when Yuan Chang and colleagues announced its discovery in December 1994 (1). Since then, about 200 publications on this new herpesvirus have appeared, which indicates the growing interest in it. Without this discovery through the representational difference analysis, this conference might not have been convened. Chang et al. (1) called the new virus "Kaposi's sarcoma-associated herpesvirus (KSHV)" because they discovered it in KS tissue of patients with AIDS. Schulz and Weiss (2), in a commentary on their discovery, suggested that "HHV-8" was a slightly more neutral name regarding etiology. The name does not really matter and, throughout the conference, some participants use "KSHV" and others say "HHV-8." It has been argued that, because this virus is associated not only with KS but also with other lesions, such as lymphoma, we should not call it "KSHV." But on that account we should not call HTLV-1 "human T-cell leukemia virus" anymore because it also causes the neurologic disease tropical spastic paraparesis; we should rename "hepatitis G virus" because it does not appear to cause hepatitis.
After Chang et al. (1) first identified
HHV-8 in lesions of KS of AIDS patients, we examined the presence
of HHV-8 among the different KS epidemiologic groups. Data on
the polymerase chain reaction (PCR) detection of HHV-8 in
paraffin-imbedded KS tissue are shown in Table 1.
The great majority of KS samples were positive for
the presence of this virus, whatever the epidemiologic group (3,4). If we exclude the ones that had
poor-quality DNA, as judged by weak amplification of a cellular
gene, then virtually 100% of KS samples were HHV-8
positive. Several other groups have accrued similar results.
Thus, there is genuine consensus that this virus is universally
present in KS lesions.
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When we looked for HHV-8 by in situ techniques, we observed that a majority of spindle cells showed the presence of HHV-8, although negative nuclei were also present (5). Again, several other groups have confirmed this result. For example, the presence of HHV-8 genes, antigens, and indeed viruses particles has been demonstrated by Orenstein et al. (6).
A continuing question is whether HHV-8 plays a causal role or whether it is a passenger virus. Another question is whether HHV-8, like Epstein-Barr virus, is ubiquitous in the human population or is restricted to KS groups? We favor a causal role, and a consensus is emerging that HHV-8 contributes to the pathogenesis of KS.
Using PCR techniques, some groups reported that the virus is more widespread and detected KSHV in non-KS skin tumors in immunosuppressed patients and in the semen of healthy donors. We could not detect HHV-8 in squamous cell carcinomas of the skin in immunosuppressed transplant recipients (7) or in the semen of healthy donors (8).
However, one could argue that this virus is ubiquitous and that it might become activated by angiogenesis but that it is normally latent at very low load or not expressed at all until it is activated by angiogenic cytokines or chemokines. We could not detect HHV-8 in benign hemangiosarcomas or granulomas; as a result, among angiogenic lesions (3), its expression seems to be specific to KS, although the cytokine profiles in these lesions might differ.
Nevertheless, HHV-8 is associated with other lymphoproliferative lesions. Multicentric Castleman's disease was first reported by Soulier et al. (9) in France to contain HHV-8, with 14 of 14 HIV-positive patients with Castleman's disease and a rather smaller proportion of HIV-negative patients being HHV-8 positive; we have obtained similar results, as have Dupin et al. (10), among others. Multicentric Castleman's disease is a lymphoproliferative lesion that frequently includes angiogenic proliferation and sometimes presents together with KS itself.
Better known are the primary effusion lymphomas (or body cavity-based lymphomas) first described as containing HHV-8 by Cesarman et al. (11). These lymphomas tend to grow as effusions in the pleural or pericardial cavity. They lack many of the cell surface adhesion molecules that one might expect to be present on lymphomas (12). While many primary effusion lymphomas are positive for EBV, practically all of them are positive for HHV-8. Primary effusion lymphoma cell lines have provided the basis for many studies presented at this conference on the induction, replication, and cloning of HHV-8 genes, as well as for HHV-8 serology.
With the use of primary effusion lymphoma cell lines in culture
with latent infection as an assay for immunofluorescence antibody
detection, sera from patients with KS show a punctate nuclear
staining (Fig. 1). This assay has been the
basis of several studies for first-generation serologic surveys
of HIV infection (13-16).
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These cell lines also can be induced by phorbol esters or sodium butyrate to enter a lytic viral replication in which many more of the HHV-8 proteins are expressed, and hence more antigens are there to be recognized. This induction of lytic viral protein expression should produce greater sensitivity in detection of antibodies, but the question is whether it reduces specificity. Recombinant antigen assays are not yet as sensitive as immunoflurescence assays (14).
As discussed at the beginning of this conference, the incidence
of KS is different in different parts of the world and in
different categories of patients with AIDS (17). Our serology for HHV-8 antibodies fits the same
pattern (Fig. 2). Among all the different
categories of AIDS patients from the United States and Northern
Europe, we can see that HHV-8 infection occurs most frequently in
gay men and least often in patients with hemophilia. Heterosexual
acquisition of HIV in Africa is also associated with KS.
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We showed in 1995 that HHV-8 genomes are detectable in the blood of a proportion of KS-negative, HIV-positive gay men and that their presence is strongly predictive of later development of KS (18). If we consider serology and genome detection together, there appears to be a strong link between HHV-8 infection and later development of KS. Geographically, too, the detection of HHV-8 antibodies is associated with high-incidence areas for KS (e.g., Greece, Italy, and Uganda) (19). In a collaboration with Freddy Sits in Johannesburg, South Africa, we have shown that mother-to-child transmission is an important route for acquiring HHV-8 in Africa (20).
The antigen specifying the nuclear speckle staining used in
immunofluorescence studies has recently been identified as the
HHV-8 orf 73 product (21,22). This gene
has a complex pattern of transcription, differing in latent and
lytic infections. In latent infection, a large transcript
including v-cyclin (orf 72) and K13 FLIP (i.e., FLICE inhibitory
protein) (orf 71) is evident (Fig. 3) (22).
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With regard to v-cyclin, we together with Mittnacht, Chang, and Moore (23,24), have shown that the v-cyclin protein can phosphorylate retinoblastoma protein. This phosphorylation is mediated mainly through cdk6 (24,25). HHV-8 v-cyclin can also block the function of the Rb protein as a tumor suppressor in a transfection assay in osteosarcoma cells that lack Rb (23). This is an example of one HHV-8 gene that could be potentially oncogenic. Others include the genes for a G-coupled protein receptor, an interferon response element (26,27), and apoptosis inhibitors such as the v-FLIP (K13), v-bcl-2, and v-IL-6. HHV-8 also encodes for chemokine homologues (v-MIP-I and v-MIP-II), which we have shown to have HIV-inhibitory activity (26) and angiogenic potential in an in vivo assay (28).
Several of these genes are discussed in more detail in other papers delivered at this conference. A caveat is that the presence of transforming genes in a human virus does not necessarily mean that the virus is oncogenic in humans. The adenovirus genes EIA and EIB are classical oncogenes, but there is no evidence that adenoviruses cause tumors in humans. The same is true for BK papovavirus. Thus, we have to be cautious about interpreting our findings with genes when we clone them and express them in NIH3T3 cells or other experimental systems. What makes HHV-8 look increasingly guilty of causing KS and lymphoma is the combination of epidemiologic and experimental data: The prevalence of the virus is generally high in those human populations with a high incidence of KS, and the virus carries the tools to stimulate cell proliferation and to induce neovascularization.
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Acknowledgments |
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Supported by the Cancer Research Campaign and the Medical Research Council.
The work presented here is part of a much larger consortium of collaborators in epidemiology and molecular pathology as seen in the authorship of our primary publications.
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References |
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TopAbstractIntroductionReferences |
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