Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy

Objective: It is thought as a consequence of continuous replication, HIV-1 has acquired an optimal fitness state and that suboptimal antiretroviral th erapy selects for drug resistant variants which show impaired Fitness in th e absence of the drug. In this paper we studied the evolution and fitness o f viral populations appearing in a patient who received protease monotherap y. Methods: Two factors contributing to fitness, drug resistance and protease catalytic activity, were studied at the enzymatic and virological level. Results: The first drug resistant viral variants that were selected in vivo harboured one to three protease substitutions. These mutants showed reduce d protease activity and consequently a reduction in viral replication capac ity. During continued in vivo replication of these viruses in the presence si the drug, novel variants harbouring additional substitutions in the vira l protease appeared. These variants did not display any further increase in drug resistance but demonstrated clearly increased protease activity. Cons equently the replication capacity of these viruses was raised to a level at which they replicated better than the original wild-type virus. Conclusion: This study indicates that the viral population in the patient d oes not have to represent the fittest possible variants, and thus antiretro viral therapy may drive the viral population first through a lower fitness level and then to a higher fitness level. (C) 1999 Lippincott Williams & Wi lkins.