title: Wide variation in susceptibility of transmitted/founder HIV-1 subtype C Isolates to protease inhibitors and association with in vitro replication efficiency.
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.
authors.affiliation: Division of Infection and Immunity, UCL, London, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Sutherland
authors.affiliation: Emory Vaccine Centre, Atlanta GA, USA.
authors.forename: Dami A
authors.initials: DA
authors.lastname: Collier
authors.affiliation: Emory Vaccine Centre, Atlanta GA, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Claiborne
authors.affiliation: Emory Vaccine Centre, Atlanta GA, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Prince
authors.affiliation: Emory Vaccine Centre, Atlanta GA, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Deymier
authors.affiliation: Emory Vaccine Centre, Atlanta GA, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Goldstein
authors.affiliation: Emory Vaccine Centre, Atlanta GA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
authors.affiliation: Emory Vaccine Centre, Atlanta GA, USA.
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Gupta
mesh_terms: D000069446:Atazanavir Sulfate / Q000627:therapeutic use; D004261:DNA Replication / Q000187:drug effects* / Q000235:genetics; D000069454:Darunavir / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D061466:Lopinavir / Q000627:therapeutic use; D008826:Microbial Sensitivity Tests; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics; D015024:Zambia; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D000069454:Darunavir