PARTIAL INHIBITION OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE RESULTS IN ABERRANT VIRUS ASSEMBLY AND THE FORMATION OF NONINFECTIOUS PARTICLES

The production of infectious particles by human immunodeficiency virus type 1 is dependent on the accurate cleavage of its Gag and Gag/Pol p recursors by a virally encoded protease. In the absence of protease ac tivity, morphologically abnormal particles which are noninfectious are formed. Recently, inhibitors of the protease of human immunodeficienc y virus type 1 have been developed as potential therapeutic agents. We have examined the basis for the loss of infectivity at the limiting i nhibitor concentrations that are likely to be achieved in clinical set tings. We found that subtle defects in processing are correlated with profound deficits in infectivity. Further, we correlated this partiall y disrupted processing with an altered virion morphology. These data s uggest that accurate and complete processing is essential to the forma tion of infectious, morphologically normal virions and that the pathwa y by which these precursors are processed and assembled is sensitive t o partial inhibition of the protease by an inhibitor disproportionate to the effect of the inhibitor on the viral protease itself.