Effect of Raltegravir Resistance Mutations in HIV-1 Integrase on Viral Fitness

Raltegravir resistance is conferred by mutations at integrase codons 143, 148, and 155 together with associated secondary mutations. The N155H mutants emerge first, and are eventually replaced by Q148H mutants, usually in combination with G140S. These mutations have different effects on susceptibility and replication capacity, but data on the relative fitness of RAL-resistant viruses are limited. To understand the impact of the different RAL resistance pathways on viral fitness, mutations at integrase codons 74, 92, 138, 140, 148, 155, and/or 163 were introduced into HIV-1NL4-3 by site-directed mutagenesis and expressed in recombinant viruses. Relative fitness and drug susceptibility were determined in the absence or presence of RAL. In the absence of drug, RAL-resistant mutants were less fit than wild type, and the Q148H mutant was significantly less fit than the N155H mutant. Fitness was partially restored by the presence of additional RAL resistance mutations at positions G140S and E92Q or E138K, respectively. In the presence of RAL, the N155H mutant remained fitter than the Q148H mutant, but the G140S/Q148H double mutant was fitter than single mutants or the E92Q/N155H double mutant. These findings correspond well with the clinical trials data and help explain the temporal pattern of RAL resistance evolution.