REGULATION OF HIV REPLICATION BY NOVEL AMINOSTEROLS, MSI-1436 AND ITS ANALOGS

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Kinter Productive infection by HIV is known to be dependent upon numerous cellular factors and processes, particularly those involved in cellular activation and differentiation. While agents which broadly inhibit activation, such as cyclosporin, are potent suppressers of HIV replication in CD4+ T cells, they dramatically reduce the ability of T cells to proliferate and respond to antigens and other stimulatory signals. MSI-1436 and its analogs are novel aminosterols which are known to interfere with the sodium/hydrogen exchanger (NHE) isoform 3, a cellular antiporter important in the regulation of intracellular pH. At high concentrations these compounds suppress mitogenesis both in vivo and ex vivo in T cells and suppress the growth of various tumors in murine models. MSI-1436 and its analogs were found to suppress HIV and SIV replication from in vitro infected peripheral blood mononuclear cells (PBMCs) as well as to reduce HIV expression in chronically HIV-infected cell lines at concentrations which did not alter cellular proliferation or activation. In vitro isolation of HIV from PBMC obtained from HIV-infected donors that were stimulated with mitogens or recall antigens was significantly inhibited without alteration in the ability of the cells to proliferate, produce interleukin (IL)-2 or express cell surface activation antigens. In vivo, MSI-1436 was analyzed for its ability to reduce simian immunodeficiency virus (SIV) disease in pigtail macaques following establishment of chronic SIV infection. SIV viremia was not significantly altered; however, the CD4+:CD8+ T cells ratios were elevated in treated animals compared to controls. Determination of maximal blood levels of MSI-1436 revealed that efficacious concentrations were not achieved in these studies. Analyses of the effect of MSI-1436 and its analogs on HIV replication and CD4+ T-cell survival are presently being conducted in various SCID mouse models including SCID mice reconstituted with human fetal liver/thymus or with human PBL.