Title: Impact of drug resistance-associated amino acid changes in HIV-1 subtype C on susceptibility to newer nonnucleoside reverse transcriptase inhibitors
Authors: Basson AE, Rhee SY, Parry CM, El-Khatib Z, Charalambous S, De Oliveira T, Pillay D, Hoffmann C, Katzenstein D, Shafer RW, Morris L.
Journal: Antimicrob Agents Chemother,pii: AAC.04215-14:pii: AAC.04215-14 (2015)
Abstract
OBJECTIVE:
To assess the phenotypic susceptibility of NNRTI resistance associated amino acid changes to newer NNRTIs in HIV-1 subtype C.
METHODS:
A panel of 52 site-directed mutants and 38 clinically derived HIV-1 subtype C clones were created and assessed for phenotypic susceptibility to etravirine (ETR), rilpivirine (RPV), efavirenz (EFV) and nevirapine (NVP) in an in vitro single-cycle phenotypic assay.
RESULTS:
Amino acid substitutions E138Q/R, Y181I/V and M230L conferred high-level resistance to ETR while K101P and Y181I/V conferred high-level resistance to RPV. Y181C, a major NNRTI resistance-associated amino acid substitution caused decreased susceptibility to ETR and to a lesser extent RPV when combined with other mutations. This included N348I and T369I, amino acid changes in the connection domain that are not generally assessed during resistance testing. However, the prevalence of these genotypes among subtype C sequences was in most cases <1%. The more common EFV/NVP resistance substitutions, such as K103N, V106M, and G190A, had no major impact on ETR or RPV susceptibility. Low-level resistance to RPV and ETR conferred by the RPV-specific amino acid substitution E138K was not significantly enhanced in the presence of the common NRTI substitution M184V/I, unlike for EFV and NVP. Among patient samples, 97% were resistant to EFV and/or NVP while only 24% and 16% were resistant to ETR and RPV, respectively.
CONCLUSION:
Only a few, relatively rare, NNRTI resistance-associated amino acid substitutions caused resistance to ETR and/or RPV in an HIV-1 subtype C background suggesting that these newer NNRTI would be effective in NVP/EFV-experienced HIV-1 subtype C-infected patients.
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Citation: Basson AE, Rhee SY, Parry CM, El-Khatib Z, Charalambous S, De Oliveira T, Pillay D, Hoffmann C, Katzenstein D, Shafer RW, Morris L. Impact of drug resistance-associated amino acid changes in HIV-1 subtype C on susceptibility to newer nonnucleoside reverse transcriptase inhibitors Antimicrob Agents Chemother,pii: AAC.04215-14:pii: AAC.04215-14 (2015).