title: Impact of drug resistance-associated amino acid changes in HIV-1 subtype C on susceptibility to newer nonnucleoside reverse transcriptase inhibitors.
abstract: The objective of this study was to assess the phenotypic susceptibility of HIV-1 subtype C isolates, with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated amino acid changes, to newer NNRTIs. A panel of 52 site-directed mutants and 38 clinically derived HIV-1 subtype C clones was created, and the isolates were assessed for phenotypic susceptibility to etravirine (ETR), rilpivirine (RPV), efavirenz (EFV), and nevirapine (NVP) in an in vitro single-cycle phenotypic assay. The 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. These 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-associated substitutions, such as K103N, V106M, and G190A, had no major impact on ETR or RPV susceptibility. The low-level resistance to RPV and ETR conferred by E138K was not significantly enhanced in the presence of 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. Overall, 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 NNRTIs would be effective in NVP/EFV-experienced HIV-1 subtype C-infected patients.
authors.affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases (NICD), part of the National Health Laboratory Service (NHLS), Johannesburg, South Africa University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Adriaan E
authors.initials: AE
authors.lastname: Basson
authors.affiliation: Division of Infectious Diseases, Stanford University Medical Center, Stanford, California, USA.
authors.forename: Soo-Yon
authors.initials: SY
authors.lastname: Rhee
authors.affiliation: Antiviral Unit Virus Reference Department, Health Protection Agency (HPA), London, United Kingdom MRC/UCL Center for Medical Molecular Virology, UCL, London, United Kingdom MRC/UVRI Research Unit on AIDS, Uganda Virus Research Institute, Entebbe, Uganda.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Parry
authors.affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases (NICD), part of the National Health Laboratory Service (NHLS), Johannesburg, South Africa Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ziad
authors.initials: Z
authors.lastname: El-Khatib
authors.affiliation: The Aurum Institute, Johannesburg, South Africa.
authors.forename: Salome
authors.initials: S
authors.lastname: Charalambous
authors.affiliation: Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Mtubatuba, South Africa.
authors.forename: Tulio
authors.initials: T
authors.lastname: De Oliveira
authors.affiliation: Antiviral Unit Virus Reference Department, Health Protection Agency (HPA), London, United Kingdom MRC/UCL Center for Medical Molecular Virology, UCL, London, United Kingdom.
authors.forename: Deenan
authors.initials: D
authors.lastname: Pillay
authors.affiliation: The Aurum Institute, Johannesburg, South Africa Johns Hopkins University, Center for TB Research, School of Medicine, Baltimore, Maryland, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: Division of Infectious Diseases, Stanford University Medical Center, Stanford, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Katzenstein
authors.affiliation: Division of Infectious Diseases, Stanford University Medical Center, Stanford, California, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
authors.affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases (NICD), part of the National Health Laboratory Service (NHLS), Johannesburg, South Africa University of the Witwatersrand, Johannesburg, South Africa lynnm@nicd.ac.za.
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
mesh_terms: D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D018894:Reverse Transcriptase Inhibitors