Emergence of drug resistant HIV variants with mutations in the protease gene and gag cleavage sites during indinavir therapy

In a group receiving indinavir for 12 weeks, and subsequently in combination with RT nucleoside inhibitors there were two categories of response. In one, suppression of virus replication occurred and has persisted for 90 weeks (bDNA less than 500 particles/ml). While virus was below detectable levels, it could be characterized by PCR amplification of the low levels of virus in plasma, or of proviral DNA in peripheral blood mononuclear cells. No changes were seen in the protease gene that were associated with drug resistance. In the second group, emergence of protease drug resistant variants was indicated by a rebound in blood virus levels that followed the initial decline. Virus in plasma showed a sequential acquisition of protease mutations at amino acids 46, 82, 54,71,89 and 90. In each of five patients there were changes in both the protease gene and the p7/p1 gag cleavage site. In three cases these changes were coincident in time and occurred as early as 6 weeks. Since optimal rates of virus replication require protease cleavage of precursor polyproteins, mutations in the cleavage site of a protein whose availability through cleavage was rate limiting, would confer on that virus a significant growth advantage. This may be a reason why variants that we have characterized have preferentially selected for alterations at the p7/p1 cleavage site. Three important factors to monitor in protease therapy are differences in the structures of the proteases at the start of therapy, and changes in both protease and its cleavage sites that occur during therapy.

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