RESISTANCE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TO PROTEASE INHIBITORS - SELECTION OF RESISTANCE MUTATIONS IN THE PRESENCE AND ABSENCE OFTHE DRUG

Inhibitors of the human immunodeficiency virus (HIV) protease are a pr omising class of antiviral agents that dramatically reduce HIV replica tion both in culture and in infected patients. However, as for many ot her antiviral compounds, long-term efficacy of these agents is impeded by the emergence of virus variants with increased resistance to their inhibitory action, following selection of specific mutations in the p rotease coding sequence. We have studied HIV-1 variants that emerged a t different stages of selection in the presence of the C2-symmetrical protease inhibitor ABT-77003. The selection of variants was a gradual process during which mutations accumulated at different sites in the p rotease, generating virus populations with increasing levels of resist ance to the drug. The initially selected viruses had a low level of re sistance as well as a markedly reduced replicative capacity. Further a ccumulation of mutations at secondary sites led to an improvement in b oth drug resistance and replication. In spite of their reduced infecti vity, partially selected virus populations did not readily revert to w ild-type when serially passaged in drug-free conditions. Instead, even in the absence of drug, secondary mutations identical to those select ed in the presence of the inhibitor continued to emerge. These mutatio ns improved both the intrinsic replicative capacity of the virus and i ts level of resistance to the inhibitor, suggesting that once committe d to drug resistance, readaptation of the enzyme to its natural substr ate leads to a reduction of its sensitivity to the inhibitor.