Abstract
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.
Highlights
The successful global roll-out of antiretroviral therapy has resulted in approximately 15.8 million HIV positive individuals receiving antiretroviral therapy to date[1]
Gag cleavage sites were examined for the presence of amino acid residues that might correlate with protease inhibitors (PI) susceptibility based on previous literature[10,13] (Supplementary Table S1)
Mutation M30R was associated with higher replication capacity (RC) and appeared to be enriched in patients with reduced PI susceptibility, but 30 R was only present in three high RC patients in this cohort. This is the first study to describe the variation in PI susceptibility of HIV-1 subtype C using patient specific Gag-Protease sequences from PI-naïve adults
Summary
The successful global roll-out of antiretroviral therapy has resulted in approximately 15.8 million HIV positive individuals receiving antiretroviral therapy to date[1]. Boosted PIs have been used extensively in resource-rich settings as part of first-line regimens and have similar efficacy to NNRTI based regimens[7,8]. Despite their widespread use, the viral genetic correlates of PI resistance are not fully understood. To date there are no data on the in vitro PI susceptibility of newly transmitted subtype C clinical isolates from untreated adults as measured using full-length replication competent chimeric viruses differing only in their patient-derived gag-protease genes[19]. We sought to study PI susceptibility and in vitro replication efficiency in a unique panel of subtype C chimeric viruses generated from acutely infected individuals enrolled in the Zambia-Emory HIV Research Project (ZEHRP) transmission cohort
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