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UC781, a thiocarboxanilide nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), inhibited RT DNA polymerase activity in vitro with marked potency. Significant inhibition was noted at a 1:1 molar ratio of UC871 to RT, characteristic of a tight-binding inhibitor. Infectivity of the HIV-1(IIIB) laboratory strain was eliminated in a concentration-dependent manner following short exposure of isolated virion particles to UC781. Neither nevirapine nor certain other carboxanilide nonnucleoside inhibitors were effective in this manner. Endogenous reverse transcription in UC781-treated virus particles was markedly reduced. Treatment of chronically HIV-1-infected H9 cells with UC781 did not alter virus production, but the infectivity of the virus produced by the cells during drug exposure was markedly reduced. Moreover, the infectivity of nascent virus produced by the UC781-treated H9 cells after removal of exogenous drug was dramatically attenuated. Similarly, pretreatment of peripheral blood lymphocytes isolated from HIV-infected patients abolished the infectivity of virus produced by these cells after removal of exogenous drug, as measured by coculture experiments with uninfected cord blood mononuclear cells, indicating the utility of UC781 against a variety of clinical HIV samples. Importantly, preincubation of uninfected MT2 cells with UC781 rendered these cells refractory to subsequent HIV infection in the absence of extracellular drug, an effect that persisted for several days following removal of exogenous drug. These unique properties of UC781 indicate that this nonnucleoside inhibitor may have considerable promise for use in retrovirucidal formulations to minimize the spread of HIV from infected to noninfected individuals.

journal of virology

Chemical barriers to human immunodeficiency virus type 1 (HIV-1) infection: retrovirucidal activity of UC781, a thiocarboxanilide nonnucleoside inhibitor of HIV-1 reverse transcriptase