Characterization of the E138K Resistance Mutation in HIV-1 Reverse Transcriptase Conferring Susceptibility to Etravirine in B and Non-B HIV-1 Subtypes

Asahchop, Eugene L.; Oliveira, Maureen; Wainberg, Mark A.; Brenner, Bluma G.; Moïsi, Daniela; Toni, Thomas; Tremblay, Cécile

doi:10.1128/aac.01192-10

Cited by 53 publications

(66 citation statements)

References 47 publications

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“…We found that when present alone, the E138K, M184I, and M184V mutations each reduced the RC of HIV-1 3-to 4-fold compared to that of the WT in the absence of drug. This observation confirms and extends a previous report that found a 2-fold decrease in the RC in E138K mutants (2). In contrast, the combined presence of E138K and either M184I or M184V resulted in an RC equal to that of the WT.…”

Section: Discussionsupporting

confidence: 81%

“…Although initial studies of in vitro selection with ETV reported a variety of resistance mutations (25), a more recent report using clinical isolates from several different HIV-1 subtypes found that the E138K mutation was selected in all isolates and was usually the first mutation to emerge (2). A number of amino acid substitutions at RT position 138, including E138K, were identified in HIV-1 after the failure of ETV in the phase 3 trials (22).…”

Section: Discussionmentioning

confidence: 99%

“…We examined the interactions among the E138K and M184I/V mutations in a single viral genetic backbone (NL4-3), and different results might be obtained in different backbones. However, the E138K mutation appears to have similar effects in a variety of viral isolates and subtypes (2). The fitness profiles and growth competition experiments were performed in the presence of one or two drugs, whereas most antiretroviral regimens involve threedrug combinations.…”

Section: Discussionmentioning

confidence: 99%

“…Etravirine (ETV; formerly TMC125) and rilpivirine (RPV; formerly TMC278) are potent next-generation NNRTIs that retain activity against efavirenz (EFV)-resistant viruses carrying the K103N mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) (1,3); both are diarylpyrimidine (DAPY) compounds. The E138K mutation, which emerges both in vitro and in vivo, confers resistance to ETV and RPV (2,3,22,23). Although in vitro passage experiments suggested that resistance to ETV and RPV emerges more slowly than resistance to first-generation NNRTIs (e.g., nevirapine [NVP] or EFV) (3,25), this finding has not been confirmed in clinical trials, which show the emergence of ETV and RPV resistance at the time of virologic failure in most patients treated with these drugs (17,18).…”

mentioning

confidence: 99%

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Interaction of Reverse Transcriptase (RT) Mutations Conferring Resistance to Lamivudine and Etravirine: Effects on Fitness and RT Activity of Human Immunodeficiency Virus Type 1

Hu¹,

Kuritzkes²

2011

J Virol

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Resistance to the nonnucleoside reverse transcriptase inhibitors etravirine and rilpivirine (RPV) is conferred by the E138K mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT).Clinical trials of RPV administered with lamivudine or emtricitabine showed the emergence of E138K together with M184I, which confers lamivudine and emtricitabine resistance in most patients with virologic failure. To understand why M184I was favored over M184V, we determined the drug susceptibility, infectivity, relative fitness, and reverse transcriptase activity of HIV-1 carrying E138K/M184I or E138K/M184V mutations. Whereas the replication capacity (RC) of the single mutants was reduced compared to that of the wild type (WT), the RC of the two double mutants was comparable to that of the WT in the absence of drug. The RC of the E138K/M184I mutant in the presence of etravirine was significantly greater than that of the E138K and E138K/M184V mutants; the RC of the double mutants was greater than that of the M184I or M184V mutant. Fitness profiles and growth competition experiments showed that the E138K/M184I mutant had a significant replicative advantage over the E138K/M184V mutant in the presence of etravirine and lamivudine. The virion-associated RT activity of the E138K, M184I, or M184V virus was significantly reduced compared to that of the WT, whereas the RT activity of the E138K/M184I virus was significantly greater than that of the WT or E138K/M184V virus. These results suggest that the E138K and M184I/V mutations are mutually compensatory and may explain the frequent occurrence of E138K/M184I after the virologic failure of rilpivirine-, lamivudine-, and emtricitabine-containing regimens.Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of combination antiretroviral therapy. Etravirine (ETV; formerly TMC125) and rilpivirine (RPV; formerly TMC278) are potent next-generation NNRTIs that retain activity against efavirenz (EFV)-resistant viruses carrying the K103N mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) (1, 3); both are diarylpyrimidine (DAPY) compounds. The E138K mutation, which emerges both in vitro and in vivo, confers resistance to ETV and RPV (2,3,22,23). Although in vitro passage experiments suggested that resistance to ETV and RPV emerges more slowly than resistance to first-generation NNRTIs (e.g., nevirapine [NVP] or EFV) (3, 25), this finding has not been confirmed in clinical trials, which show the emergence of ETV and RPV resistance at the time of virologic failure in most patients treated with these drugs (17, 18).Most antiretroviral regimens include the cytosine analogs lamivudine (3TC) or emtricitabine (FTC) administered as fixed-dose combinations together with zidovudine (ZDV) or abacavir (ABC) in the case of ZDV/3TC and ABC/3TC or with tenofovir (TDF) in the case of TDF/FTC. Resistance to 3TC and FTC is conferred by a valine or isoleucine substitution for the methionine normally found at position 184, which lies in the ...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Interaction of Reverse Transcriptase (RT) Mutations Conferring Resistance to Lamivudine and Etravirine: Effects on Fitness and RT Activity of Human Immunodeficiency Virus Type 1

Hu¹,

Kuritzkes²

2011

J Virol

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“…Cells in 24-well tissue culture plates were infected with recombinant viral clones at a similar multiplicity of infection (MOI). Selection for viral resistance mutations was performed by using increasing concentrations of RT inhibitors at starting concentrations below the 50% effective concentration (EC 50 ), as described previously (3,38). As controls, all viruses were simultaneously passaged without drugs.…”

Section: Chemicalsmentioning

confidence: 99%

Subunit-Selective Mutational Analysis and Tissue Culture Evaluations of the Interactions of the E138K and M184I Mutations in HIV-1 Reverse Transcriptase

Oliveira

Quashie

et al. 2012

J Virol

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The emergence of HIV-1 drug resistance remains a major obstacle in antiviral therapy. M184I/V and E138K are signature mutations of clinical relevance in HIV-1 reverse transcriptase (RT) for the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and emtricitabine (FTC) and the second-generation (new) nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV), respectively, and the E138K mutation has also been shown to be selected by etravirine in cell culture. The E138K mutation was recently shown to compensate for the low enzyme processivity and viral fitness associated with the M184I/V mutations through enhanced deoxynucleoside triphosphate (dNTP) usage, while the M184I/V mutations compensated for defects in polymerization rates associated with the E138K mutations under conditions of high dNTP concentrations. The M184I mutation was also shown to enhance resistance to RPV and ETR when present together with the E138K mutation. These mutual compensatory effects might also enhance transmission rates of viruses containing these two mutations. Therefore, we performed tissue culture studies to investigate the evolutionary dynamics of these viruses. Through experiments in which E138K-containing viruses were selected with 3TC-FTC and in which M184I/V viruses were selected with ETR, we demonstrated that ETR was able to select for the E138K mutation in viruses containing the M184I/V mutations and that the M184I/V mutations consistently emerged when E138K viruses were selected with 3TC-FTC. We also performed biochemical subunit-selective mutational analyses to investigate the impact of the E138K mutation on RT function and interactions with the M184I mutation. We now show that the E138K mutation decreased rates of polymerization, impaired RNase H activity, and conferred ETR resistance through the p51 subunit of RT, while an enhancement of dNTP usage as a result of the simultaneous presence of both mutations E138K and M184I occurred via both subunits.

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Clinical and analytical relevance of NNRTIs minority mutations on viral failure in HIV‐1 infected patients

Mohamed

Ravet

Camus

et al. 2013

Journal of Medical Virology

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The objective of this study was to assess the analytical and clinical relevance of minority variants using a new pyrosequencing (PSQ) assay and to detect minor variants with frequencies below the current 20% clinical setting limit. A PSQ approach for detecting and quantifying mutations was developed for the analysis of 14 codons of the human immunodeficiency virus (HIV) reverse transcriptase (RT) gene below the limit of conventional sequencing. Ten patients who experienced virological failure (VF) after a first-line regimen of lamivudine, tenofovir, and either efavirenz, nevirapine, or etravirine, as well as 10 controls patients without VF, were included in this retrospective study. Baseline plasma and plasma from the time of VF were assessed using Sanger sequencing and PSQ methods. The analytical sensitivity for the detection of minor sequence variants is 5%. At baseline, no minority variant was detected in 10/10 patient controls using both the Sanger sequencing and PSQ assays, whereas, two patients who failed therapy had baseline non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations that were not detected by the standard genotyping. At the time of VF, standard genotyping detected mutations in four out of the 10 VF patients, whereas, PSQ detected mutations in five out of the 10 VF patients. Clinically, minority mutations at a 10% level of detection can be assessed efficiently by pyrosequencing and used as a suitable predictor of the evolution of viral populations. These traits allow for a better interpretation of data analysis, which can help clinicians in providing a suitable treatment for HIV.

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Characterization of the E138K Resistance Mutation in HIV-1 Reverse Transcriptase Conferring Susceptibility to Etravirine in B and Non-B HIV-1 Subtypes

Cited by 53 publications

References 47 publications

Interaction of Reverse Transcriptase (RT) Mutations Conferring Resistance to Lamivudine and Etravirine: Effects on Fitness and RT Activity of Human Immunodeficiency Virus Type 1

Interaction of Reverse Transcriptase (RT) Mutations Conferring Resistance to Lamivudine and Etravirine: Effects on Fitness and RT Activity of Human Immunodeficiency Virus Type 1

Subunit-Selective Mutational Analysis and Tissue Culture Evaluations of the Interactions of the E138K and M184I Mutations in HIV-1 Reverse Transcriptase

Clinical and analytical relevance of NNRTIs minority mutations on viral failure in HIV‐1 infected patients

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