Effect of protease inhibitors on HIV-1 maturation and infectivity

The effects of HIV-1 protease inhibitors on proteolytic processing and infectivity of virions produced from lymphocytes chronically infected with the virus were studied. Protease inhibition was detected by the accumulation of the polyprotein precursors Pr55gag and Pr160gag-pol and their cleavage intermediates. Immunoblot analysis demonstrated that while the processing of Pr55gag was largely irreversible, cleavage of Pr160gag-pol proceeded once the inhibitor was removed, although it was not completed during 96 h of subsequent observation. Virions produced during exposure of cells to protease inhibitors regained some degree of infectivity post-withdrawal of the inhibitor, suggesting that the processing of Pr160gag-pol following drug withdrawal resulted in the production of those enzymes necessary to enable at least limited viral replication. When cells were exposed to a protease inhibitor for 72 h then the inhibitor withdrawn, a lag phase of up to 24 h occurred before these cells produced virions with equivalent infectivity to virus produced from cells not exposed to drug. These observations may reflect a clinical situation likely to occur as trough plasma concentrations of protease inhibitors fall below the IC100 for HIV, highlighting the need for adherence to drug regimens containing these inhibitors.