title: Connection domain mutations in HIV-1 reverse transcriptase do not impact etravirine susceptibility and virologic responses to etravirine-containing regimens.
abstract: Connection domain mutations (CDMs) in HIV-1 reverse transcriptase (RT) alter susceptibility to some nucleoside/nonnucleoside RT inhibitors (NRTIs/NNRTIs). Their effects on susceptibility and virologic responses to etravirine were analyzed. Seventeen CDMs were evaluated: L283I, E312Q, G333D, G333E, G335C, G335D, N348I, A360I, A360T, A360V, V365I, T369I, A371V, A376S, I393L, E399D, and E399G. CDM prevalence and effects on virologic responses were analyzed retrospectively using clinical data. The effects on etravirine susceptibility were assessed in clinical samples and confirmed using site-directed mutants. The most prevalent CDMs (>10%) were A371V, E399D, A376S, N348I, A360T, G333E, and L283I. CDM presence was positively correlated with thymidine analogue-associated mutations, but not with NNRTI resistance-associated mutations (RAMs). The presence or number of CDMs did not significantly reduce etravirine susceptibility, although small reductions were seen in samples with G333D, N348I, A360V, T369I, and A376S. N348I, E399G, and N348I/T369I were associated with reduced etravirine susceptibility when present with K103N, L100I, or Y181C. N348I or T369I was associated with reduced etravirine susceptibility when present with K101P or K103R/V179D. Virologic responses to an etravirine-containing regimen were slightly diminished when G333D, G335D, or A376S was present, but this was not confirmed in subgroups with higher baseline resistance or without etravirine RAMs. CDMs alone do not confer substantial reductions in etravirine susceptibility but can further reduce etravirine susceptibility in combination with certain NNRTI mutations. Since virologic responses to etravirine were not affected by CDMs, the clinical impacts of these mutations on etravirine susceptibility appear to be minimal.
authors.affiliation: Monogram Biosciences, Inc., South San Francisco, California, USA.
authors.forename: Soumi
authors.initials: S
authors.lastname: Gupta
authors.forename: Johan
authors.initials: J
authors.lastname: Vingerhoets
authors.forename: Signe
authors.initials: S
authors.lastname: Fransen
authors.forename: Lotke
authors.initials: L
authors.lastname: Tambuyzer
authors.forename: Hilde
authors.initials: H
authors.lastname: Azijn
authors.forename: Arne
authors.initials: A
authors.lastname: Frantzell
authors.forename: Roger
authors.initials: R
authors.lastname: Paredes
authors.forename: Eoin
authors.initials: E
authors.lastname: Coakley
authors.forename: Steven
authors.initials: S
authors.lastname: Nijs
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Christos J
authors.initials: CJ
authors.lastname: Petropoulos
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schapiro
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Gaston
authors.initials: G
authors.lastname: Picchio
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009570:Nitriles; D010641:Phenotype; D011724:Pyridazines / Q000494:pharmacology*; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase