Human immunodeficiency virus (HIV) is the etiological agent for AIDS and individuals infected with HIV usually go through a prolonged latent period without developing any clinical disease. The factors contributing to the termination of latency are not well understood and it is believed that infection with other viruses may play an important role by providing the activation signals to terminate the HIV latency. Among the viruses that have been studied, the newly identified human herpesvirus-6 (HHV-6) has been implicated as an important viral cofactor. HHV-6 is isolated frequently from patients with AIDS and more importantly, HHV-6 infects the same cell type as HIV, namely, CD4+ T cells and monocytes, both in vivo and in vitro. Our long term objectives are to understand the biology of HIV and HHV-6 interactions, the role played by HHV-6 in enhancing the pathogenesis of HIV Infection and vice versa. Our studies show that the promoter in the long terminal repeats (LTR) of HIV-1 can be transactivated by infection of T cells with HHV-6 and four transactivating gene fragments of group A HHV-6(GS) (pZVB70, pZVH14, pZVB10 and pGD41) have been identified. The highest level of transactivation was seen with the 22kb pZVB70 DNA clone and we have identified a 143 amino acids ORF (B7O1) within the pZVB70 DNA clone and a nuclear phosphoprotein P41 encoded within the pGD41 clone as the transactivating proteins. The NF-kB binding sites in the HIV-LTR appear to be important for the transactivation mediated by these two proteins, and the B701 protein but not the P41 protein can induce TNF-alpha in monocytes. Preliminary studies also show that HIV-1 expression can activate group A HHV-6(GS) viral expression in T cells. Our goals for the next funding period are: (1) to define the mechanism by which the two HHV- 6 gene products, B701 and P41, transactivate the HIV LTR dependent gene expression; (2) to determine the domains of the B701 and P41 essential for transactivation, and to identify and characterize the native proteins in HHV-6 infected cells; (3) to identify and characterize other group A HHV- 6(GS) gene products with transactivating function, and to define the mechanism of transactivation; (4) to identify the specific HIV gene(s) involved in the induction of HHV-6 gene expression. The studies proposed here are significant as they will generate important information about how HHV-6 can act as a co-factor, the gene products involved and their mechanism of actions, which will eventually lead to design ways to block such interactions.
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