Effects of human immunodeficiency virus type 1 resistance to protease inhibitors on reverse transcriptase processing, activity, and drug sensitivity

Human immunodeficiency virus type 1 (HIV-1) variants resistant to protease inhibitors often display a reduced replicative capacity as a result of an i mpairment of protease function. Such fitness-impaired viruses display Gag p recursor maturation defects. Here, we report that some protease inhibitor-r esistant viruses also display abnormalities in the processing of reverse tr anscriptase (RT) by the protease. In three recombinant viruses carrying res istant protease sequences from patient plasma, we observed a marked decreas e in the amount of mature RT subunits and of particle-associated RT activit y compared to their parental pretherapy counterparts. We investigated the p ossibility that a decrease in the amount of particle-associated mature RT c ould affect the sensitivity of the corresponding virus to RT inhibitors. We observed a twofold increase of sensitivity to zidovudine (AZT) when a viru s which carried AZT mutations was processed by a resistant protease. Intere stingly, the presence of AZT-resistance mutations partially rescued the rep lication defect associated with the mutated protease. The interplay between resistance to protease inhibitors and to RT inhibitors described here may be relevant to the therapeutic control of HIV-1 infection.