The role of HHV-8 in Kaposi's sarcoma

Abstract

The epidemiology of Kaposi's sarcoma (KS) amongst North American and Northern European patients with AIDS suggests that an infectious agent other than HIV is involved in its pathogenesis. Several lines of evidence indicate that human herpesvirus 8 (HHV–8), also termed Kaposi's sarcoma associated herpesvirus, is the sought after agent. DNA of HHV–8 is invariably found in all forms of KS where the virus is present in the KS spindle cell. In contrast, HHV–8 DNA is not regularly detected in most other malignancies. Antibodies against HHV–8 are more frequently found in groups at risk of KS, and HHV–8 seroconversion precedes KS development. Several HHV–8 genes have been identified that exhibit transforming potential in cell culture systems. In addition, the virus encodes and induces several cytokines and angiogenic factors. This is of particular interest as models of KS pathogenesis developed before the discovery of HHV-8 emphasized the importance of inflammatory cytokines. Although the expression pattern of viral genes in KS is not certain yet, it appears likely that the pathogenetic role of HHV–8 in KS may be rather complex and differs from other virus-induced malignancies.@9cBackground: Kaposi's sarcoma among AIDS patients—evidence for a sexually transmitted infection@21K aposi's sarcoma (ks) was—and outside of the HIV-infected population still is—a rare disease in Europe and the United States. In its `classical' form it afflicts elderly men of Mediterranean or Eastern European origin, where it may progress slowly over several years. The unusual occurrence of a more aggressive variant of KS in young homosexual men was one of the first signs of the beginning of AIDS epidemic.1Out of the 90,990 persons with AIDS that were reported to the Centers for Disease Control until March 1989, 13,616 or 15% suffered from Kaposi's sarcoma.2KS was thus at least 20,000 times more common in persons with AIDS than expected in the general population. The peculiar epidemiology of KS in different HIV-transmission groups clearly indicated that an environmental or transmis- sible agent other than HIV must be involved in KS pathogenesis.2Most notably, whereas approximately 20% of homo- and bisexual AIDS-patients developed KS, only 1% of age- and sex-matched men with hemophilia suffered from this uncommon tumor (Figure 1). This triggered a broad search for behavioral factors3and infectious agents associated with increased risk for KS. Several known human viruses were identified in KS tissues by PCR, including human cytomegalovirus,4human herpesvirus 6,5human papilloma viruses 16/186and BK virus.7However, none of these factors or viruses was found to be linked consistently to KS.8–10Representational difference analysis, a PCR-based method targeted at the identification of differences between two complex genomes, was published in 1993.11Application of this technique to Kaposi's sarcoma resulted in the identification of two short DNA fragments from a new herpesvirus by Yuan Chang, Patrick Moore and their colleagues.12This virus, now termed human herpesvirus 8 (HHV-8) or Kaposi's sarcoma-associated herpesvirus (KSHV), is the first known human member of the genus Rhadinovirus or γ2-herpesviruses.<fig 1>