biostudies-otherSutherland KANIAID NIH HHSMedical Research CouncilWellcome Trust38153https://www.ebi.ac.uk/biostudies/studies/S-EPMC5128871The gag gene is highly polymorphic across HIV-1 subtypes and contributes to susceptibility to protease inhibitors (PI), a critical class of antiretrovirals that will be used in up to 2 million individuals as second-line therapy in sub Saharan Africa by 2020. Given subtype C represents around half of all HIV-1 infections globally, we examined PI susceptibility in subtype C viruses from treatment-naïve individuals. PI susceptibility was measured in a single round infection assay of full-length, replication competent MJ4/gag chimeric viruses, encoding the gag gene and 142 nucleotides of pro derived from viruses in 20 patients in the Zambia-Emory HIV Research Project acute infection cohort. Ten-fold variation in susceptibility to PIs atazanavir and lopinavir was observed across 20 viruses, with EC50s ranging 0.71-6.95?nM for atazanvir and 0.64-8.54?nM for lopinavir. Ten amino acid residues in Gag correlated with lopinavir EC50 (p?<?0.01), of which 380?K and 389I showed modest impacts on in vitro drug susceptibility. Finally a significant relationship between drug susceptibility and replication capacity was observed for atazanavir and lopinavir but not darunavir. Our findings demonstrate large variation in susceptibility of PI-naïve subtype C viruses that appears to correlate with replication efficiency and could impact clinical outcomes.biostudies-otherEurope PMCUnknown6Scientific reportsPMC5128871MC_PC_13056R01 AI064060MC_U117573805206440R37 AI051231Hunter EGupta RKSutherland KAPrince JLGoldstein RACollier DADeymier MJClaiborne DTfalseWide variation in susceptibility of transmitted/founder HIV-1 subtype C Isolates to protease inhibitors and association with in vitro replication efficiency.The gag gene is highly polymorphic across HIV-1 subtypes and contributes to susceptibility to protease inhibitors (PI), a critical class of antiretrovirals that will be used in up to 2 million individuals as second-line therapy in sub Saharan Africa by 2020. Given subtype C represents around half of all HIV-1 infections globally, we examined PI susceptibility in subtype C viruses from treatment-naïve individuals. PI susceptibility was measured in a single round infection assay of full-length, replication competent MJ4/gag chimeric viruses, encoding the gag gene and 142 nucleotides of pro derived from viruses in 20 patients in the Zambia-Emory HIV Research Project acute infection cohort. Ten-fold variation in susceptibility to PIs atazanavir and lopinavir was observed across 20 viruses, with EC50s ranging 0.71-6.95?nM for atazanvir and 0.64-8.54?nM for lopinavir. Ten amino acid residues in Gag correlated with lopinavir EC50 (p?<?0.01), of which 380?K and 389I showed modest impacts on in vitro drug susceptibility. Finally a significant relationship between drug susceptibility and replication capacity was observed for atazanavir and lopinavir but not darunavir. Our findings demonstrate large variation in susceptibility of PI-naïve subtype C viruses that appears to correlate with replication efficiency and could impact clinical outcomes.2016-01-01T00:00:00Z2016 Nov2019-03-27T02:30:12Z2019-03-27T02:30:12ZS-EPMC51288712790108510.1038/srep38153