The HIV-1 integrase genotype strongly predicts raltegravir susceptibility but not viral fitness of primary virus isolates.

Methods: : Recombinant viruses included integrase, protease-reverse transcriptase or the complete pol-coding region from three patients whose raltegravir-containing regimen had failed. The first had the mutations G140S+Q148H+S230N, the second had Y143R+G163R and the third had no evidence of genotypic resistance in integrase. Primary virus isolates were obtained from peripheral blood mononuclear cells. In-vitro phenotypic resistance and changes in replication capacity were assessed.

Results: : Virus isolates, and integrase-recombinant and pol-recombinant viruses from the patients harboring integrase resistance mutations showed a decrease in raltegravir susceptibility, with no differences between them. Defects in viral fitness were modulated by resistance mutations within protease, reverse transcriptase and integrase, which were further compensated by regions outside pol. Moreover, protease-reverse transcriptase rescued replication capacity of viruses containing integrase resistance mutations, although integrase was unable to compensate defects in replication capacity caused by protease-reverse transcriptase resistance mutations.

Conclusion: : Virus isolates, and integrase-recombinant and pol-recombinant viruses from the patients harboring integrase resistance mutations showed a decrease in raltegravir susceptibility, with no differences between them. Defects in viral fitness were modulated by resistance mutations within protease, reverse transcriptase and integrase, which were further compensated by regions outside pol. Moreover, protease-reverse transcriptase rescued replication capacity of viruses containing integrase resistance mutations, although integrase was unable to compensate defects in replication capacity caused by protease-reverse transcriptase resistance mutations.