) Gene fragments from several distinct regions of a novel herpesvirus genome referred to as HHV-8 or KSHV have been found consistently in AIDS Kaposi s sarcoma (KS), body cavity B-cell lymphomas (BCBL) and multicentric Castleman's disease, as well as in non-AIDS-associated endemic African and classical Mediterranean KS and some immunosuppressed transplant patients. DNA sequence analysis has revealed that HHV-8 is most closely related to the squirrel monkey gamma-2 class genome of herpesvirus saimiri. Although its identity as an authentic human infectious pathogen has yet to be formally validated, expression of HHV-8 genes is likely to be a contributing factor in the growth of KS lesions. The applicant has been involved in (a) identifying novel genes within the HHV-8 genome from a BCBL lambda DNA clone library, (b) examining sequence variability of HHV-8 """"""""isolates"""""""" from many different KS and other tumor sources, and (c) preparing cDNA libraries from KS and induced BCBL sources. Results to date indicate that HHV-8 encodes a novel combination of animal herpesvirus-specific genes that include diverse homologues of the cellular GCR cytokine receptor, cyclin d, bcl-2, DHFR, TS, IL-6 and MIP-1 proteins, some of which are also found in the T-cell lymphotrophic herpesvirus saimiri, and an IE1-like ring class zinc finger motif protein similar to that found in the bovine gamma-2 class herpesvirus (BHV-4). Furthermore, overall HHV-8 sequence variability may be equivalent to that in EBV, and there appear to be two distinct subgroups of the virus, but many United States AIDS-associated isolates are virtually identical. The goals in this application are (1) to continue to define the genome organization, intactness, and gene content of HHV-8 viral DNA obtained from different KS and BCBL sources; (2) to develop in situ hybridization and antibody reagents to detect expression of known HHV-8 genes in KS tumor tissue; (3) to examine the molecular biology of the virus in cell culture to identify immediate-early regulatory genes; (4) to carry out in vitro functional assays for the potential cytokines, enzymes, cyclin and IE ring finger transactivator proteins that may play roles in KS and BCBL tumors, and (5) to begin to dissect the molecular mechanisms involved in latency, cell transformation, DNA replication, and other functionally relevant virus:cell interactions associated with HHV-8 genes in AIDS-associated tumors.
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