It was previously found that certain nonnucleoside
reverse transcriptase inhibitors (NNRTI) possess virucidal activity against human immunodeficiency virus type 1 (HIV-1), and it was suggested that the tight-binding mode of inhibition of
reverse transcriptase might be important for this virucidal activity (Borkow et al., J. Virol. 71:3023-3030, 1997). To test this, we compared six different NNRTI, including three tight-binding NNRTI, namely
UC781,
efavirenz (EFV) (
Sustiva), and 5-chloro-3-phenylsulfonylindole-2-carboxamide (CSIC), and three rapid-equilibrium NNRTI,
delavirdine (DLV) (
Rescriptor),
nevirapine (NVP) (
Viramune), and
UC84, in a variety of virucidal tests. Incubation of isolated HIV-1 virions with
UC781, EFV, or CSIC rapidly inactivated the virus, whereas DLV, NVP, and
UC84 were ineffective in this respect. Exposure of H9+ cells chronically infected by HIV-1 to the tight-binding NNRTI abolished the infectivity of nascent virus subsequently produced by these cells following removal of extracellular
drug, thereby preventing cell-to-cell virus transmission in the absence of exogenous
drug. In contrast, cell-to-cell transmission of HIV was blocked by DLV, NVP, and
UC84 only when the
drug remained in the extracellular medium. Pretreatment of uninfected lymphocytoid cells with
UC781, EFV, or CSIC, but not DLV, NVP, or
UC84, protected these cells from subsequent HIV-1
infection in the absence of extracellular
drug. The protective effect was dependent on both the dose of NNRTI and the viral load. The overall virucidal efficacy of the tight-binding NNRTI tested was CSIC >
UC781 approximately EFV. We conclude that the tight-binding mode of inhibition is an essential characteristic for virucidal NNRTI and that
antiviral potency is an insufficient predictor for virucidal utility of NNRTI.