Although there is abundant data establishing the human immunodeficiency virus (HIV) as the etiologic agent of AIDS, the factors that determine which individuals will develop AIDS, less severe symptomatic infection or mild HIV disease for months or years progress to AIDS is also unknown. Human cytomegalovirus (HCMV) is a major pathogen in AIDS, is known to infect the same cells as HIV, and is frequently proposed as an important cofactor for the development and/or progression of AIDS. In our preliminary experiments, we have found that HCMV infection can markedly affect the HIV infection in tissue culture. We have also found that HIV infection is enhanced in cell infected with an amphotropic retrovirus and have evidence that HIV pseudotypes with amphotropic envelope proteins may be formed. We hypothesize that coinfection of peripheral blood mononuclear cells by HIV and either HCMV or other viruses can affect HIV entry into cells and affect the gene expression of both viruses at either a transcriptional or posttranscriptional level, thereby contributing to the development and progression of AIDs. We further hypothesize that infection of the same cell by HIV and a second enveloped virus may lead to alterations in the HIV envelope-forming pseudotypes, thus expanding the tissue tropism and pathogenicity of HIV. The objectives of the proposed studies are to elucidate the molecular interactions of HIV and HCMV, specifically in monocyte/macrophages, glial cells, and peripheral blood mononuclear cells. In particular, we will examine the effect of dual infection by HIV and HCMV with respect to viral gene expression, virus production, and potential HIV pseudotype formation with HCMV envelope proteins. The molecular basis of the interaction between in cis-acting regulatory regions of the HIV genome and trans-acting factors induced by the HCMV infection or specified by HCMV immediate early genes will be further examined by transient expression assays in these cells. In addition, we propose to create a packaging CEM cell line expression amphotropic retrovirus proteins, which will be used to produce HIV pseudotypes with expanded cellular tropism. The HIV progeny from this packaging cell line can be used for efficient infection of CD4- cell and examination of the HIV/HCMV interaction in such cells. Finally, we will assay the blood from AIDS patients during periods of HCMV viremia for the presence of HIV pseudotypes. The long- range goal of this research is to gain an understanding of the role of viral cofactors in AIDs, thus providing the basis for development of strategies for prevention and treatment.
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