Mutations in human immunodeficiency virus type 1 reverse transcriptase that make it sensitive to degradation by the viral protease in virions are selected against in patients.

Mutations in the thumb subdomain of reverse transcriptase (RT) of HIV-1 can cause this enzyme to be degraded in virions by the viral protease (PR). Many of these mutations confer a temperature-sensitive phenotype on RT and viral replication. The degradation of RT by PR appears to take place after Gag-Pol has been processed. We show here that mutations in other parts of RT, including the RNase H domain, can make RT PR-sensitive and temperature-sensitive. These data explain why some mutations in the RNase H domain, which had little or no effect on the polymerase activity of purified recombinant RT, had a profound effect on viral titer. Because the PR-sensitive phenotype significantly reduced viral titer, we previously suggested that these mutations would be selected against in patients. We also show that RT mutations that are known to confer a temperature sensitive phenotype are rarely found in the Stanford database.