In 1994, Chang et al used representational difference analysis (RDA) to search for DNA sequences present in AIDS-associated KS but not in adjacent normal skin. Using this approach, they were able to identify a then unknown human g-herpesvirus in KS tissue, which they called the Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) . KSHV belongs to the genus Rhadinovirus, and its genomic structure is most similar to the closely related lymphotropic g-herpesviruses Epstein-Barr virus (EBV), the only other known human her-pesvirus associated with human cancers. Compelling evidence points to KSHV as the infectious etiologic agent for KS: (i) Epidemiological studies have established a pattern of KSHV infection that precedes KS development and overlaps with KS risks. (ii) Examination of KS biopsies revealed that KSHV DNA is present in KS tumor (spindle) cells and in endothelial cells lining vascular spaces of KS lesion. (iii) In vitro studies have demonstrated that KSHV can infect and transform endothelial cells (thought to be premalignant for KS). Of note, these studies further revealed that KSHV was present in only a subset of cultured immortalized endothelial cells, suggestive of a paracrine mechanism in the immortalization of uninfected cells . (iv) Unlike HIV, KSHV has been found to be associated with all four forms of KS (classic, iatrogenic, endemic, and AIDS-related), in addition to two other neoplastic disorders: primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD) . However, while PEL and MCD primarily involve KSHV-infected lymphocytes, KS involves KSHV infection of endothelial cells. As KSHV is a lymphotropic herpesvirus, it remains to be determined how and why KSHV makes the transition from lymphocyte to endothelial cell.
Following endothelial infection, KSHV can enter one of two pathways: the latent cycle or the lytic cycle. In the latent cycle, the KSHV genome is tethered to the host cell chromosome as an independent episome. Replication of the host cell results in replication of the viral genome, which is passed on to each daughter cell. The few genes that are expressed during latency function primarily to maintain the episomal viral DNA and to promote host-cell proliferation, thereby promoting replication of the viral genetic material within the latently infected host cell. Reentry into the lytic cycle (viral reactivation) is usually triggered in latently infected cells under special circumstances. Upon reactivation, viral early genes—required for the transcription and translation of the viral genome—are first expressed, which then facilitate the expression of viral structural proteins (late genes). Viral genes that play a role in sustaining host-cell survival or in modulating the host immune response are also expressed during the lytic cycle, promoting efficient production of viral progeny and ensuring successful viral propagation.
Current efforts are now focused on defining the mechanism whereby this virus causes KS. KSHV contains more than 90 open reading frames (ORFs), including several homologs to mammalian proteins likely pirated by KSHV from its cellular host. Further investigation has revealed that several of these genes bear potential for KS pathogenesis . These include both latent and lytic genes that may be directly transforming or could contribute to KS indirectly by promoting the production of angiogenesis-activating growth factors and inflammatory cytokines.
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