Human immunodeficiency viruses (HIVs) may comprise a spectrum of human retroviruses with varying potential for latency, virulence and pathogenicity. These capacities may be governed, in part, by their genetic structure. This project aims to analyze the structure and function of the genomes of the highly pathogenic [HIV-1, HIV-2(ROD)] and weakly pathogenic [HIV-2(ST)] HIVS. Since much of the virus regulation is centered in its long terminal repeat (LTR), relevant to latency and virulence, and the envelope gene plays a major role in pathogenicity, the focus of this study is the LTR-based regulatory elements and regulatory genes (tat), and the envelope gene. Also relevant are the properties of these viruses to be activated by non-HIV factors, such as T cell activation, and by concomitant infection with some DNA virus. We have recently presented the novel observation of two enhancer elements in HIV-2 that regulate virus expression. Contrary to the previous belief that the designated enhancer (containing the NFKB binding site) is the response element, as is the case for HIV-1, it is the second enhancer of HIV-2 that is mainly responsible for activation of HIV-2 gene expression by T cell activators. The second enhancer interacts with a specific transcriptional factor apparently distinct from the NFKB protein. The presence of two enhancers in HIV-2 raises the possibility that these enhancers may function differentially depending on the cell phenotype and environmental factors and this may underlie virus latency. We have also shown that HIV-2 expression is activated by the transactivator gene (IE2) of the cytomegalovirus which may act as a cofactor in causation of AIDS. In an attempt to map determinants of fusogenicity and pathogenicity of HIV, analysis of the chimeric genomes between HIV-2(ST) and HIV-2(ROD) revealed that the env gene is a major determinant of cytopathicity and presumably pathogenicity. Studies with other env based chimeric genomes now in progress may allow a finer and more precise definition of the critical domains.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
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Division of Cancer Epidemiology and Genetics
United States
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