Identification of a novel resistance (E40F) and compensatory (K43E) substitution in HIV-1 reverse transcriptase

Huigen, Marleen C. D. G.; Ham, Petronella M van; Graaf, Loek de; Kagan, Ron M.; Boucher, Charles A.; Nijhuis, Monique

doi:10.1186/1742-4690-5-20

Cited by 12 publications

(8 citation statements)

References 46 publications

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“…This increase is probably only transient and is expected to be reversed at reinitiation of therapy. Our findings of stable RC values over the 12-week course of salvage therapy in no-ARDFP patients confirm previous observations that accumulation of resistance-associated mutations during partially suppressive HAART (as in many patients in that group) is not likely to induce further RC decline, probably because secondary 'compensatory' mutations appear [28,29]. Among patients not undergoing a treatment interruption, PSS was correlated with baseline RC and was highly predictive of virologic response to salvage ARV regimen up to week 48, after controlling for other baseline variables: RC, CD4 cell count and viral load.…”

Section: Discussionsupporting

confidence: 79%

Predictive value of HIV‐1 replication capacity and phenotypic susceptibility scores in antiretroviral treatment‐experienced patients

Bedimo¹,

Kyriakides

Brown³

et al. 2012

HIV Medicine

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ObjectivesThe aim of the study was to determine the prognostic value of HIV replication capacity (RC) for subsequent antiretroviral (ARV) treatment response in ARV-experienced patients. MethodsRC and phenotypic resistance testing were performed at baseline and week 12 on plasma samples from patients randomized to undergo a 12-week ARV drug-free period (ARDFP) or initiate immediate salvage therapy (no-ARDFP group) in the Options in Management with Antiretrovirals (OPTIMA) trial. Dichotomous and incremental phenotypic susceptibility scores (dPSSs and iPSSs, respectively) were calculated. The predictive value of RC and PSS for ARV therapy response and/or ARDFP was evaluated using multivariate regression analysis and Pearson correlations. ResultsIn 146 no-ARDFP subjects, baseline RC (50.8%) did not change at week 12 and was not correlated with CD4 cell count or viral load changes at week 12 (P = 0.33 and P = 0.79, respectively) or at week 24 (P = 0.96 and P = 0.14, respectively). dPSS predicted virological but not CD4 cell count response to ARV therapy at weeks 12, 24 and 48 (P = 0.002, P < 0.001 and P = 0.005, respectively). RC was significantly correlated with dPSS and iPSS at baseline, but did not increase their predictive value. In the 137 ARDFP patients, RC increased significantly (from 52.4 to 85.8%), but did not predict CD4 cell count and viral load changes during ARDFP (P = 0.92 and P = 0.26, respectively). RC after ARDFP did not predict subsequent CD4 cell count and viral load changes 12 weeks following ARV treatment reinitiation (P = 0.90 and P = 0.29, respectively). ConclusionsWe found no additional predictive value of replication capacity for virological or immunological responses (above what PSS provides) in patients undergoing salvage ARV treatment.Keywords: antiretroviral therapy, HIV, phenotypic susceptibility score, replication capacity, resistance Accepted 27 October 2011 IntroductionIn clinical trials of effective HIV combination antiretroviral (ARV) regimens, the majority of study participants maintained virological suppression for 3-7 years [1][2][3]. However, the proportion of patients experiencing treatment failure in real-life clinical settings is reported to be somewhat higher [4][5][6], and these patients have an increased risk of HIV disease progression. Incomplete virological suppression is expected to lead to the emergence and accumulation of drug-resistant strains, which might jeopardize the success of future treatment options [7][8][9][10][11]. It is therefore important to improve our understanding of the In addition to genotypic and phenotypic testing, replication capacity (RC) is regularly used by clinicians when deciding on the strategy for the management of these treatment-experienced patients. A number of trials have determined that temporary interruption of ARV treatment is a strategy that leads to rapidly increased plasma HIV RNA, decreased CD4 T-cell count and increased risk for clinical progression [12][13][14]. However, interruption of a failing regimen results in a rapid inc...

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Section: Discussionsupporting

confidence: 79%

Predictive value of HIV‐1 replication capacity and phenotypic susceptibility scores in antiretroviral treatment‐experienced patients

Bedimo¹,

Kyriakides

Brown³

et al. 2012

HIV Medicine

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“…For example, Huigen et al found that the K43E mutation alone did not increase the levels of resistance, but showed a compensatory role when combined with E40F. 18 A study by Cane et al showed that K43E was detected in only 1% of HIV-1 patients with no TAMs but in 24% of samples with four or more TAMs, 16 whereas in the present study the mutation was seen in 83.3% of newly diagnosed, therapynaive HIV-1 patients who were infected with CRF01_AE, and in none of the CRF07_BC patients. It is possible that the K43E change was a subtype-specific polymorphic mutation that was found more frequently in CRF01_AE than CRF07_BC.…”

Section: Discussionmentioning

confidence: 99%

Transmitted Antiretroviral Drug Resistance and Thumb Subdomain Polymorphisms Among Newly HIV Type 1 Diagnosed Patients Infected with CRF01_AE and CRF07_BC Virus in Guangdong Province, China

Yang

Liu

Zhang

et al. 2012

AIDS Research and Human Retroviruses

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The aim of this study was to elucidate the prevalence of transmitted drug-resistant (TDR) mutations and reverse transcriptase (RT) thumb subdomain polymorphisms in CRF01_AE and CRF07_BC virus among newly diagnosed, therapy-naive HIV-1 patients in Guangdong Province, China. One hundred and sixty-four samples were collected in the Guangzhou Eighth People's Hospital. The entire protease gene and 300 codons of the entry part of the reverse transcriptase were amplified and sequenced. Furthermore, genotypic drug resistance, polymorphisms, and their phylogeny were analyzed. According to eligibility criteria, seven samples were excluded, and 119 of 157 (75.8%) samples (84 CRF01_AE and 35 CRF07_BC) were amplified and sequenced successfully. The prevalence of TDR identified in the present study was 6.7% [8/119, 95% confidence interval (CI) 1.8-11.6%]. Three major resistance mutations, K103N, M184V, and Y188L, each of which caused more than one drug resistance, appeared in only two patients; the prevalence [1.7 % (2/119)] was relatively low. Until now, this is the first observation of the five newly identified accessory mutations, V35T, K43E, V60I, K122E, and E203D, and seven thumb subdomain polymorphisms, A272P, K277R, K281R, T286A, E291D, V292I, and I293V, in the RT gene in China. These findings provide useful information for guidance on the antiretroviral therapy (ART) policy in China where therapeutic options are still limited.

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“…Several of these mutations occur at known NRTI resistance positions: K65N, D67G/E/S/T, K70Q/N/G/S/T, L74I, V75M/A/S, and K219N/R/W/ D/H (2,4,11,25,30,37). Others are at novel positions in the 5= polymerase coding domain: E40F, K43E/Q/N, E44D/A, V118I, E203K, H208Y, D218E, K223Q/E, and L228H/R (9, 12, 33) (13,30). Finally, several mutations 3= to the polymerase coding domain facilitate nucleotide excision, presumably by slowing enzymatic translocation, allowing more time for nucleoside reverse transcriptase inhibitor (NRTI) excision (19).…”

Section: Discussionmentioning

confidence: 99%

Standardized Comparison of the Relative Impacts of HIV-1 Reverse Transcriptase (RT) Mutations on Nucleoside RT Inhibitor Susceptibility

Melikian

Rhee

Taylor

et al. 2012

Antimicrob Agents Chemother

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h Determining the phenotypic impacts of reverse transcriptase (RT) mutations on individual nucleoside RT inhibitors (NRTIs) has remained a statistical challenge because clinical NRTI-resistant HIV-1 isolates usually contain multiple mutations, often in complex patterns, complicating the task of determining the relative contribution of each mutation to HIV drug resistance. Furthermore, the NRTIs have highly variable dynamic susceptibility ranges, making it difficult to determine the relative effect of an RT mutation on susceptibility to different NRTIs. In this study, we analyzed 1,273 genotyped HIV-1 isolates for which phenotypic results were obtained using the PhenoSense assay (Monogram, South San Francisco, CA). We used a parsimonious feature selection algorithm, LASSO, to assess the possible contributions of 177 mutations that occurred in 10 or more isolates in our data set. We then used least-squares regression to quantify the impact of each LASSO-selected mutation on each NRTI. Our study provides a comprehensive view of the most common NRTI resistance mutations. Because our results were standardized, the study provides the first analysis that quantifies the relative phenotypic effects of NRTI resistance mutations on each of the NRTIs. In addition, the study contains new findings on the relative impacts of thymidine analog mutations (TAMs) on susceptibility to abacavir and tenofovir; the impacts of several known but incompletely characterized mutations, including E40F, V75T, Y115F, and K219R; and a tentative role in reduced NRTI susceptibility for K64H, a novel NRTI resistance mutation. In a previous study, we applied several data-mining approaches to quantify associations between NRTI-associated HIV-1 drug resistance mutations and in vitro susceptibility data (24). About 630 susceptibility test results were available for abacavir (ABC), didanosine (ddI), lamivudine (3TC), stavudine (d4T), and zidovudine (AZT), and 350 were available for tenofovir (TDF). In that study, we used a predefined list of nonpolymorphic NRTI-selected mutations to reduce the number of independent variables influencing NRTI susceptibility. Here we analyze a data set that is about twice as large and uses two regression methods in tandem: one to identify genotypic predictors of NRTI susceptibility from the many RT mutations present in the data set (rather than relying on a predefined list of mutations, as we did previously) and one to quantify the impact of RT mutations on NRTI susceptibility. In addition, we used several approaches to determine whether models that included statistical interactions among NRTI resistance mutations improved the prediction of reductions in NRTI susceptibility. MATERIALS AND METHODSHIV-1 isolates. We analyzed HIV-1 isolates in the HIV Drug Resistance Database (HIVDB) (22) for which in vitro NRTI susceptibility testing had been performed by the PhenoSense (Monogram, South San Francisco, CA) assay (20). About 35% of the test results were from studies published previously by other laboratories; 65% were from s...

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Identification of a novel resistance (E40F) and compensatory (K43E) substitution in HIV-1 reverse transcriptase

Abstract: In conclusion, we have identified a novel resistance (E40F) and compensatory (K43E) change in HIV-1 RT. Further research is indicated to analyse the clinical importance of these changes.

Cited by 12 publications

References 46 publications

Predictive value of HIV‐1 replication capacity and phenotypic susceptibility scores in antiretroviral treatment‐experienced patients

Predictive value of HIV‐1 replication capacity and phenotypic susceptibility scores in antiretroviral treatment‐experienced patients

Transmitted Antiretroviral Drug Resistance and Thumb Subdomain Polymorphisms Among Newly HIV Type 1 Diagnosed Patients Infected with CRF01_AE and CRF07_BC Virus in Guangdong Province, China

Standardized Comparison of the Relative Impacts of HIV-1 Reverse Transcriptase (RT) Mutations on Nucleoside RT Inhibitor Susceptibility

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