The genome of HHV-8 consists of a 140.5-kb length of DNA unique coding region flanked by multiple G+C-rich 801-bp terminal repeat sequences (Russo et al., 1996). The genome contains a number of “pirated” genes that have very close cellular homologs in a manner analogous to that seen with retrovirally transduced oncogenes (Chapter 4). Table 12.9 lists several of these genes with their cellular homolog and possible function (Boshoff and Weiss, 1998). However, expression of the viral genome in Kaposi’s sarcoma is quite limited (Zhong et al., 1996). One of the genes expressed is analogous to transforming proteins found in other herpesviruses and may be related to transformation by HHV-8 (Lee et al., 1998). Latently infected cells have multiple copies of circularized HHV-8 DNA maintained as episomes in a manner similar to that of EBV (cf. Ballestas et al., 1999). A latency-associated nuclear antigen appears to mediate the efficient
Figure 12.18 Estimated prevalence of serum antibodies against HHV-8–associated latent nuclear anti- gens in 40 patients with AIDS-associated Kaposi sarcoma in relation to the number of months prior to the diagnosis of the neoplasm. (After Gao et al., 1996, with permission of the authors and publisher.)
aInterferon regulatory family.
bG protein–coupled receptor homolog.
Adapted from Boshoff and Weiss, 1998, with permission of the authors and publisher.
persistence of extrachromosomal DNA of HHV-8 in the same way that the EBV nuclear antigen performs this function (Ballestas et al., 1999). As noted in Table 12.9, a number of the pirated genes code for proteins involved in cell growth and death. This may actually serve to modulate the growth of neoplastic, latently infected cells of Kaposi sarcoma and other HHV-8–induced neoplasms (Dittmer and Kedes, 1998). A model of the pathogenesis of Kaposi sarcoma is seen in Figure 12.19, indicating the production of various growth factors and related proteins in cells early during infection, with subsequent transformation to sarcoma cells and continued produc- tion of autocrine growth factor (Emmanoulides et al., 1996). HHV-8 may also induce lysis of infected cells with production of virus (Ensoli and Sirianni, 1998). This model of the pathogene- sis of the development of Kaposi sarcoma after infection with HHV-8 is quite analogous to that for the development of Burkitt lymphoma after infection with EBV except for the fact that, based on present knowledge, it is unlikely that there is a high incidence of subclinical infections with HHV-8 in the general population throughout the world.