The acquired immune deficiency syndrome (AIDS) is reaching epidemic proportions in the United States. The disease is caused by a retrovirus, commonly called HTLV-III/LAV, that is tropic and cytopathic for T lymphocytes. Infection with the AIDS virus is dependent upon the action of an RNA dependent DNA polymerase (reverse transcriptase). In contrast, the replication and repair of DNA in the target T lymphocyte is mediated primarily, if not exclusively, by DNA polymerase-alpha. This major enzymatic difference between virus and host is a logical candidate for the selective development of anti-viral agents. Indeed, several deoxynucleoside analogs have recently been described that apparently inhibit viral replication by this mechanism. Unfortunately, many deoxynucleosides are not phosphorylated efficiently by the resting T lymphocytes that are potential targets for HTLV-III/LAV infection. An ideal agent for the treatment of AIDS should accumulate in both non-dividing and proliferating T lymphocytes, as well as inhibit reverse transcriptase. Previous experiments in this laboratory have shown that deoxyadenosine, and related compounds, are selectively phosphorylated and """"""""trapped"""""""" by human T lymphocytes, compared to other cell types. The purpose of the present studies is to design and evaluate specific analogs of deoxyadenosine that are similarly taken up by T lymphocytes, that resist degradation by cellular enzymes, and that render the T cells resistant to infection by HTLV-III/LAV. Intially, the uptake and metabolism of each deoxynucleoside will be examined in cultured human CEM T lymphoblasts, in mutants deficient in individual purine metabolic enzymes, and in normal T cells. Subsequently, the capability of selected agents to inhibit the in vitro infection of wild type and enzyme deficient CEM T cells by HTLV-III/LAV will be assessed. Finally, the ability of the drugs to protect normal peripheral blood T cells from HTLV-III/LAV infection will be determined. The anti-viral studies will be performed in association with Dr. Douglas Richman at the San Diego Veterans Administration Medical Center, with whom the principal investigator has an established collaboration.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Scripps Research Institute
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