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Antimicrob Agents Chemother. 2015 Feb;59(2):960-71. doi: 10.1128/AAC.04215-14. Epub 2014 Nov 24.

Impact of drug resistance-associated amino acid changes in HIV-1 subtype C on susceptibility to newer nonnucleoside reverse transcriptase inhibitors.

Author information

1
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.
2
Division of Infectious Diseases, Stanford University Medical Center, Stanford, California, USA.
3
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.
4
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.
5
The Aurum Institute, Johannesburg, South Africa.
6
Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Mtubatuba, South Africa.
7
Antiviral Unit Virus Reference Department, Health Protection Agency (HPA), London, United Kingdom MRC/UCL Center for Medical Molecular Virology, UCL, London, United Kingdom.
8
The Aurum Institute, Johannesburg, South Africa Johns Hopkins University, Center for TB Research, School of Medicine, Baltimore, Maryland, USA.
9
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.

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.

PMID:
25421485
PMCID:
PMC4335849
DOI:
10.1128/AAC.04215-14
[Indexed for MEDLINE]
Free PMC Article

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