HIV-1 infection of cells vial the CD4 molecule can lead to cell death and the immune dysfunction defined as AIDS. Elimination of the CD4+ cells is not an immediate consequence of HIV infection, however, suggesting that alterations in CD4+ T cell function may be involved in the pathogenesis of AIDS. Our efforts to explore the interaction of HIV-1 with CD4+ T lymphocytes will focus on two issues. First, we will examine the CD4 gene and its product from an evolutionary viewpoint focusing on CD4 expression, structure and function. The phylogenetic distance between chickens, mice and humans will be exploited to identify important regions of the CD4 gene and protein on the basis of evolutionary conservation. Starting with monoclonal antibodies to the chicken CD4 homologue, we will isolate and characterize the CD4 cDNA and chromosomal genes. Chicken CD4 DNA and protein sequences will be compared with mouse and human CD4 homologues and other members of the immunoglobulin supergene family. The expression of CD4 mRNA and protein, during normal ontogeny and after experimental manipulation of T cell subpopulations, will be examined using the cDNA probe and CD4 monoclonal antibodies. If a shorter CD4 mRNA is found in chicken brain, the cDNA corresponding to this transcript will be isolated and characterized. The deduced protein sequence will be used to produce antibodies for localization of the smaller putative brain CD4 protein. In a second series of experiments, we will study the activation requirements and function of virgin and primed subsets of human CD4+ T cells, and examine how these characteristics are affected by HIV-1 infection. Monoclonal antibodies will be used to separate CD4+ T cells into virgin (CD45R+) and memory (CD45R-) subpopulations. Our initial observations indicate that the activation requirements of these two subsets are very different. Here we will explore the details of their activation using a selected panel of lymphokines and monoclonal antibodies to signal transducing surface molecules. The effects of HIV-1 and isolated viral envelope proteins on the activation and function of virgin and primed T cells will be analyzed, and the requirements for virus production by both populations examined. Prevalence and infection of the two T cell supopulations will be examined in HIV-1 inactivation individuals. The ability lymphokines will be assessed. These two lines of investigation should yield information on the interactions between CD4+ T lymphocyte and HIV-1 and improve our understanding of the pathogenesis of AIDS.
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