Effect of HIV-1 Integrase Resistance Mutations When Introduced into SIVmac239 on Susceptibility to Integrase Strand Transfer Inhibitors

摘要: ABSTRACT Studies on the in vitro susceptibility of SIV to integrase strand transfer inhibitors (INSTIs) have been rare. In order determine SIVmac239 INSTIs and characterize genetic pathways that might lead drug resistance, we inserted various (IN) mutations had selected with HIV under pressure raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG) into IN gene SIV. We evaluated effects these viral infectivity. Sequence alignments HIV-1 isolates showed a high degree homology conservation each catalytic triad key residues involved resistance. Each G118R, Y143R, Q148R, R263K, G140S/Q148R mutations, when introduced SIV, impaired infectiousness replication fitness compared wild-type virus. Using TZM-bl cells, demonstrated Q148R N155H mutational conferred resistance EVG (36- 62-fold, respectively), whereas R263K also displayed moderate (12-fold). contrast, all yielded low levels RAL. The combination high-level both RAL (>300- 286-fold, respectively). DTG remained fully effective against site-directed mutants except G118R R263K. Thus, INSTI resulted similar phenotype. These findings suggest may share profiles could be useful nonhuman primate model for studies INSTIs. IMPORTANCE goal our project was establish whether are likely same as those responsible HIV. Our data answer this question affirmative show can probably serve good animal an early indicator possible emergent cause treatment failure. An SIV-primate remains invaluable tool investigating questions related potential role therapy, transmission, pathogenesis, present study will facilitate above.