A C2 symmetry-based
HIV protease inhibitor,
A77003, exerts potent
antiviral activity against a wide spectrum of HIV isolates in vitro. In this study, we asked whether
A77003 could cause irreversible conformational changes to HIV-1, whether the amounts of
viral RNA and p24
capsid protein per virion were altered, and how the infectivity of the virus produced in the presence of the
drug was affected. We found that the number of viral particles and per-virion
viral RNA content of the virus produced in the presence of
A77003 did not significantly differ from those of the virus produced in the absence of the
drug, whereas significant morphological changes were observed as assessed by transmission electron microscopy. However, the virus produced in the presence of
A77003 contained substantially less p24gag
protein per virion particle as compared to those produced in the absence of the
drug or in the presence of AZT. Virions produced in the presence of
A77003 showed up to 50-fold less infectious capability in subsequent tissue culture than control virions produced in the absence of
drug or in the presence of AZT. This reduction in infectivity was maintained for at least 10 days in culture. The present data suggest that
A77003 impairs
HIV-1 protease-mediated Gag processing, interferes with the assembly and maturation of the virus, and leads to an irreversible loss of the infectivity of the virus, although a low but positive level of reversion to infectivity during the 10-day assay occurs. These features of
A77003 (and perhaps similar
HIV protease inhibitors as well) anti-HIV activity should represent desirable properties for
antiviral therapy of
AIDS and related diseases.