) Human herpesvirus-8 (HHV-8), also called Kaposi's sarcoma-associated virus (KSHV), was first identified in 1994 in AIDS Kaposi's sarcoma biopsies. Kaposi's sarcoma (KS) was a relatively rare angiogenic neoplasm that dramatically increased in incidence with the onset of the AIDS epidemic. Approximately 20 percent of gay and bisexual men with AIDS develop KS. HHV-8 is also consistently associated with two other malignancies in AIDS patients: Multicentric Castleman's disease and a subset of non-Hodgkin's lymphomas called primary effusion lymphomas (PELs) or body cavity based lymphomas (BCBLs). PELs have the unusual feature that the majority are co-infected with both HHV-8 and another human gamma herpesvirus Epstein-Barr virus (EBV). HHV-8 and EBV each encode multiple growth stimulatory genes and the potential exists for inter-virus interactions that modulate the program of HHV-8 or EBV gene expression to allow the development of this particular malignancy. A goal of this research project is to better understand the consequences of dual infection in PELs. A number of the HHV-8 genes whose products might be anticipated to contribute to malignant cell growth are expressed during lytic viral replication rather than during latent infection. The circumstances in which these HHV-8 growth stimulatory genes are expressed is relevant to an understanding of their contribution to HHV-8 associated pathogenesis and an examination of the viral regulation of lytic HHV-8 growth stimulatory genes is also proposed.
The specific Aims of this proposal are:
Aim 1. EBV latency gene expression, promoter usage, genome copy number and status (episomal or integrated) will be examined in PEL cell lines. The possibility that HHV-8 proteins such as LANA and vIRF can modulate EBV latency promoter activity will be examined. A genetic assay for the contribution of HHV-8 latency genes to PEL development will be established.
Aim 2. The HHV-8 latency protein LANA will be characterized to determine its contribution to HHV-8 latency and tumorigene- sis.
Aim 3. The extent to which the lytic HHV-8 growth stimulatory genes and drug targets thymidine kinase and phosphotransferase are under viral regulatory control will be examined.
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