Session 27Oral Abstract Presentations Antiretroviral Drug Resistance Session Day and Time: Thursday 10 - 11:45 am Presentation Time: 10:45 Room: Ballroom C
144 Novel Drug Resistance Profiles in Non-B Subtype HIV-1 Infections D. Turner*1, B. Brenner1, B. Spira1, J. Schapiro2, M. Songok1, M. A. Wainberg1 1McGill AIDS Ctr, Lady Davis Inst, Jewish Gen Hosp, Montreal, Canada and 2Stanford Univ Sch of Med, Palo Alto, CA
Background: Despite the expansion of HIV-1 non-B infections worldwide, there is limited information on the effects of subtype genetic diversity on virological or treatment responses. This study characterizes clade-related mutations within the reverse transcriptase (RT) and protease (PR) genes that may impact on responses to antiretroviral drugs (ARVs) and the evolution of drug resistance.
Methods: Genotypic analysis of RT and PR was performed on clade A (n = 20), AE (n = 8), AG (n = 7), C (n = 40), D (n = 6) and G (n = 2) variants. Comparison to reference clade B strains identified nucleotide changes, accessory mutations and primary mutations conferring drug resistance. Effects of in vitro and in vivo ARV pressure on mutational profiles were determined. Cell-based phenotypic assays ascertained degree of resistance to ARVs of select mutations.
Results: Several clade-specific nucleotide changes and mutations were observed at sites known to be involved in drug resistance. Within the PR region, non-B clades almost always harbored the M36I polymorphism. Clade C infections uniquely harbored a G48G (GGA) silent mutation whereas clade A/G variants expressed the K20I protease accessory mutation. Within RT, numerous mutations were identified at sites associated with resistance to thymidine analogues (TAMs) and non-nucleoside RT inhibitors (NNRTIs). All treatment-na´ve subtype B isolates harbored GTA at codon 106, while GTG (valine) was generally present in drug-na´ve clade C viruses. In 3 of 3 EFV-experienced patients with clade C infections, a novel NNRTI resistance mutation, V106M, emerged. In cell-culture selection experiments using eight wild-type subtype C isolates, the V106M (GTG?ATG) resistance mutation arose under conditions of pressure with EFV but not NVP of DLV. This V106M mutation conferred high-level (100-1000 fold) resistance to all 3 NNRTIs. A T215T (ACC?ACT) silent mutation was present in clade A and A/E infections while generally absent in clade A/G, B, C, D, and G, infections. This clade A polymorphism was associated with novel T215F/N mutations (ACT?TTT/AAT) in 3 of 3 d4T-experienced patients.
Conclusions: This study identifies novel mutations within non-clade B variants that have the potential to confer high-level resistance to ARV. Polymorphisms among non-B viruses may be implicated in differential drug responses and evolutionary patterns of drug resistance.