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Combination of V106I and V179D polymorphic mutations in human immunodeficiency virus type 1 reverse transcriptase confers resistance to efavirenz and nevirapine but not etravirine.

ABSTRACT: Etravirine (ETV) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) introduced recently for salvage antiretroviral treatment after the emergence of NNRTI-resistant human immunodeficiency virus type 1 (HIV-1). Following its introduction, two naturally occurring mutations in HIV-1 RT, V106I and V179D, were listed as ETV resistance-associated mutations. However, the effect of these mutations on the development of NNRTI resistance has not been analyzed yet. To select highly NNRTI-resistant HIV-1 in vitro, monoclonal HIV-1 strains harboring V106I and V179D (HIV-1(V106I) and HIV-1(V179D)) were propagated in the presence of increasing concentrations of efavirenz (EFV). Interestingly, V179D emerged in one of three selection experiments from HIV-1(V106I) and V106I emerged in two of three experiments from HIV-1(V179D). Analysis of recombinant HIV-1 clones showed that the combination of V106I and V179D conferred significant resistance to EFV and nevirapine (NVP) but not to ETV. Structural analysis indicated that ETV can overcome the repulsive interactions caused by the combination of V106I and V179D through fine-tuning of its binding module to RT facilitated by its plastic structure, whereas EFV and NVP cannot because of their rigid structures. Analysis of clinical isolates showed comparable drug susceptibilities, and the same combination of mutations was found in some database patients who experienced virologic NNRTI-based treatment failure. The combination of V106I and V179D is a newly identified NNRTI resistance pattern of mutations. The combination of polymorphic and minor resistance-associated mutations should be interpreted carefully.

SUBMITTER: Gatanaga H

PROVIDER: S-EPMC2849364 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Combination of V106I and V179D polymorphic mutations in human immunodeficiency virus type 1 reverse transcriptase confers resistance to efavirenz and nevirapine but not etravirine.

Gatanaga Hiroyuki H Ode Hirotaka H Hachiya Atsuko A Hayashida Tsunefusa T Sato Hironori H Oka Shinichi S

Antimicrobial agents and chemotherapy 20100201 4

Etravirine (ETV) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) introduced recently for salvage antiretroviral treatment after the emergence of NNRTI-resistant human immunodeficiency virus type 1 (HIV-1). Following its introduction, two naturally occurring mutations in HIV-1 RT, V106I and V179D, were listed as ETV resistance-associated mutations. However, the effect of these mutations on the development of NNRTI resistance has not been analyzed yet. To select h ...[more]

PMID: 20124001

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Project description:BackgroundThe catalytically active 66-kDa subunit of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) consists of DNA polymerase, connection, and ribonuclease H (RNase H) domains. Almost all known RT inhibitor resistance mutations identified to date map to the polymerase domain of the enzyme. However, the connection and RNase H domains are not routinely analysed in clinical samples and none of the genotyping assays available for patient management sequence the entire RT coding region. The British Columbia Centre for Excellence in HIV/AIDS (the Centre) genotypes clinical isolates up to codon 400 in RT, and our retrospective statistical analyses of the Centre's database have identified an N348I mutation in the RT connection domain in treatment-experienced individuals. The objective of this multidisciplinary study was to establish the in vivo relevance of this mutation and its role in drug resistance.Methods and findingsThe prevalence of N348I in clinical isolates, the time taken for it to emerge under selective drug pressure, and its association with changes in viral load, specific drug treatment, and known drug resistance mutations was analysed from genotypes, viral loads, and treatment histories from the Centre's database. N348I increased in prevalence from below 1% in 368 treatment-naïve individuals to 12.1% in 1,009 treatment-experienced patients (p = 7.7 x 10(-12)). N348I appeared early in therapy and was highly associated with thymidine analogue mutations (TAMs) M41L and T215Y/F (p < 0.001), the lamivudine resistance mutations M184V/I (p < 0.001), and non-nucleoside RTI (NNRTI) resistance mutations K103N and Y181C/I (p < 0.001). The association with TAMs and NNRTI resistance mutations was consistent with the selection of N348I in patients treated with regimens that included both zidovudine and nevirapine (odds ratio 2.62, 95% confidence interval 1.43-4.81). The appearance of N348I was associated with a significant increase in viral load (p < 0.001), which was as large as the viral load increases observed for any of the TAMs. However, this analysis did not account for the simultaneous selection of other RT or protease inhibitor resistance mutations on viral load. To delineate the role of this mutation in RT inhibitor resistance, N348I was introduced into HIV-1 molecular clones containing different genetic backbones. N348I decreased zidovudine susceptibility 2- to 4-fold in the context of wild-type HIV-1 or when combined with TAMs. N348I also decreased susceptibility to nevirapine (7.4-fold) and efavirenz (2.5-fold) and significantly potentiated resistance to these drugs when combined with K103N. Biochemical analyses of recombinant RT containing N348I provide supporting evidence for the role of this mutation in zidovudine and NNRTI resistance and give some insight into the molecular mechanism of resistance.ConclusionsThis study provides the first in vivo evidence that treatment with RT inhibitors can select a mutation (i.e., N348I) outside the polymerase domain of the HIV-1 RT that confers dual-class resistance. Its emergence, which can happen early during therapy, may significantly impact on a patient's response to antiretroviral therapies containing zidovudine and nevirapine. This study also provides compelling evidence for investigating the role of other mutations in the connection and RNase H domains in virological failure.

Dataset Information

Combination of V106I and V179D polymorphic mutations in human immunodeficiency virus type 1 reverse transcriptase confers resistance to efavirenz and nevirapine but not etravirine.

Publications

Combination of V106I and V179D polymorphic mutations in human immunodeficiency virus type 1 reverse transcriptase confers resistance to efavirenz and nevirapine but not etravirine.

Similar Datasets

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