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Distinct Pattern of Thymidine Analogue Mutations with K65R in Patients Failing Tenofovir-Based Antiretroviral Therapy.

ABSTRACT: Historically, in HIV patients, the K65R mutation and thymidine analogue mutations (TAMs) have been reported to rarely coexist. We retrospectively reviewed genotype data from paired samples in a cohort of HIV-1-infected Nigerian patients failing first-line antiretroviral therapies containing zidovudine (AZT) or tenofovir (TDF). Samples for each patient were taken at initial confirmed virological failure ?1000 copies/ml (S1) and then at the latest available sample with viral load ?1000 copies/ml before switch to second line (S2). Among 103 patients failing AZT, 19 (18.4%) had TAM-1s, 29 (28.2%) TAM-2s, and 21 (20.4%) mixed TAMs by S2. In contrast, in the 87 patients failing TDF, drug resistance mutations at S2 included K65R in 56 (64.4%), TAM-1s in 1 (1.1%), and TAM-2s in 25 patients (28.7%). Interestingly, 30.4% of patients with K65R in our study developed TAMs. These were exclusively K219E?±?D67N and were not predicted to confer a resistance cost to future AZT-containing regimens.

SUBMITTER: Chaplin B

PROVIDER: S-EPMC6836671 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Distinct Pattern of Thymidine Analogue Mutations with K65R in Patients Failing Tenofovir-Based Antiretroviral Therapy.

Chaplin Beth B Imade Godwin G Onwuamah Chika C Odaibo Georgina G Audu Rosemary R Okpokwu Jonathan J Olaleye David D Meloni Seema S Rawizza Holly H Muazu Mohammad M Musa Adesola Z AZ Samuel Jay J Agbaji Oche O Ezechi Oliver O Idigbe Emmanuel E Kanki Phyllis J PJ

AIDS research and human retroviruses 20171130 2

Historically, in HIV patients, the K65R mutation and thymidine analogue mutations (TAMs) have been reported to rarely coexist. We retrospectively reviewed genotype data from paired samples in a cohort of HIV-1-infected Nigerian patients failing first-line antiretroviral therapies containing zidovudine (AZT) or tenofovir (TDF). Samples for each patient were taken at initial confirmed virological failure ≥1000 copies/ml (S1) and then at the latest available sample with viral load ≥1000 copies/ml b ...[more]

PMID: 29084434

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Project description:BACKGROUND: Thymidine analogue resistance mutations (TAMs) selected under treatment with nucleoside analogues generate two distinct genotypic profiles in the HIV-1 reverse transcriptase (RT): (i) TAM1: M41L, L210W and T215Y, and (ii) TAM2: D67N, K70R and K219E/Q, and sometimes T215F. Secondary mutations, including thumb subdomain polymorphisms (e.g. R284K) have been identified in association with TAMs. We have identified mutational clusters associated with virological failure during salvage therapy with tenofovir/emtricitabine-based regimens. In this context, we have studied the role of R284K as a secondary mutation associated with mutations of the TAM1 complex. RESULTS: The cross-sectional study carried out with > 200 HIV-1 genotypes showed that virological failure to tenofovir/emtricitabine was strongly associated with the presence of M184V (P < 10-10) and TAMs (P < 10-3), while K65R was relatively uncommon in previously-treated patients failing antiretroviral therapy. Clusters of mutations were identified, and among them, the TAM1 complex showed the highest correlation coefficients. Covariation of TAM1 mutations and V118I, V179I, M184V and R284K was observed. Virological studies showed that the combination of R284K with TAM1 mutations confers a fitness advantage in the presence of zidovudine or tenofovir. Studies with recombinant HIV-1 RTs showed that when associated with TAM1 mutations, R284K had a minimal impact on zidovudine or tenofovir inhibition, and in their ability to excise the inhibitors from blocked DNA primers. However, the mutant RT M41L/L210W/T215Y/R284K showed an increased catalytic rate for nucleotide incorporation and a higher RNase H activity in comparison with WT and mutant M41L/L210W/T215Y RTs. These effects were consistent with its enhanced chain-terminated primer rescue on DNA/DNA template-primers, but not on RNA/DNA complexes, and can explain the higher fitness of HIV-1 having TAM1/R284K mutations. CONCLUSIONS: Our study shows the association of R284K and TAM1 mutations in individuals failing therapy with tenofovir/emtricitabine, and unveils a novel mechanism by which secondary mutations are selected in the context of drug-resistance mutations.

Dataset Information

Distinct Pattern of Thymidine Analogue Mutations with K65R in Patients Failing Tenofovir-Based Antiretroviral Therapy.

Publications

Distinct Pattern of Thymidine Analogue Mutations with K65R in Patients Failing Tenofovir-Based Antiretroviral Therapy.

Similar Datasets

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