Zero prevalence of primary drug resistance-associated mutations to protease inhibitors in HIV-1 drug-naive patients in and around Aligarh, India

Azam, Mohd; Malik, Abida; Rizvi, Meher; Rai, Arvind

doi:10.3855/jidc.3480

Cited by 8 publications

(4 citation statements)

References 22 publications

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“…The polymorphisms obtained were found to be concurrent with studies carried out previously in different regions of India-North India (Chandigarh [9], Delhi [18], Aligarh [19]), West India (Mumbai [20], Pune [21][22][23]) and South India (Bengaluru [1,24], Chennai [10,[25][26][27] and Vellore [28]).…”

Section: Discussionsupporting

confidence: 86%

Polymorphisms in HIV-1 Subtype C Reverse Transcriptase and Protease Genes in a Patient Cohort from Mumbai

Dahake¹,

Mehta²,

Yadav³

2016

J Antivir Antiretrovir

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Objectives: Developed countries have been alarmed at the rates of primary/transmitted drug resistance of HIV-1. There is a debate on the validity of certain polymorphisms in HIV-1 Subtype C mutations related to consensus Subtype B sequences being associated with and sometimes mistaken as, primary resistance. In this preliminary study, we have determined polymorphisms in reverse transcriptase (RT) and protease (PR) genes of HIV-1 Subtype C from a patient cohort in Mumbai, India. Methods: The study was performed with plasma samples from twenty-four patients (antiretroviral therapy experienced as well as drug-naive) employing a 'home-brew' semi-nested reverse-transcriptase-PCR followed by sequencing and sequence analysis. The Stanford HIV drug-resistance database was used for analysis and interpretation of polymorphisms and other drug-resistance mutations. We also analysed Surveillance Drug Resistance Mutations (SDRMs) for PR gene. Results: Polymorphisms were determined at a mutational frequency of 0.1337 ± 0.042 in PR gene and 0.067 ± 0.014 in RT gene, while 16.6% and 12.5% samples harboured drug-resistance mutations in PR and RT genes respectively. Substitutions greater than 50% were at positions at L19, V82, M36, R41, L63, H69, L89 and I93 for PR gene and D121, K122, T165, K166, K173, D177, T200, Q207 and R211 for RT gene. Additionally, PR gene SDRMs were observed in 15.0% samples. Conclusions: Our findings concur with previous findings that polymorphisms in HIV-1 Subtype C from India exist and reiterate that these polymorphisms may also include a number of major and minor/accessory mutations associated with resistance. Most of the drug-resistance databases available online are based on Subtype B; hence, we recommend that HIV Subtype-specific drug-resistance databases be created to empower routine and unambiguous surveillance of drug-resistance prior to initiating antiretroviral therapy, especially while including Protease Inhibitors.

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Section: Discussionsupporting

confidence: 86%

Polymorphisms in HIV-1 Subtype C Reverse Transcriptase and Protease Genes in a Patient Cohort from Mumbai

Dahake¹,

Mehta²,

Yadav³

2016

J Antivir Antiretrovir

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“…The most frequent minor mutations observed in the PR sequence were H69K (100%) and M36L (98%), followed by L89M (58.8%), I15V (25.5%), K20R (25.5%), and T74S (17.6%). These mutations were reported with relatively the same frequencies from another study in Ethiopia [17] and India [34]. The presence of these mutations indicates a natural variation in HIV-1C virus across the globe.…”

Section: Discussionsupporting

confidence: 73%

Increased HIV-1 pretreatment drug resistance with consistent clade homogeneity among ART-naive HIV-1 infected individuals in Ethiopia

et al. 2020

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Background The development of pretreatment drug resistance (PDR) is becoming an obstacle to the success of antiretroviral therapy (ART). Besides, data from developing settings including Ethiopia is still limited. Therefore, this study was aimed to assess HIV-1 genetic diversity and PDR mutations among ART-naive recently diagnosed HIV-1 infected individuals in Addis Ababa, Ethiopia. Methods Institutional based cross-sectional study was conducted from June to December 2018 in Addis Ababa among ART-naive recently diagnosed individuals. Partial HIV-1 pol region covering the entire protease (PR) and partial reverse transcriptase (RT) regions of 51 samples were amplified and sequenced using an in-house assay. Drug resistance mutations were examined using calibrated population resistance (CPR) tool version 6.0 from the Stanford HIV drug resistance database and the International Antiviral Society-USA (IAS-USA) 2019 mutation list. Results According to both algorithms used, 9.8% (5/51) of analyzed samples had at least one PDR Mutation. PDR mutations to Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) were the most frequently detected (7.8% and 9.8%, according to the CPR tool and IAS-USA algorithm, respectively). The most frequently observed NNRTIs-associated mutations common to both algorithms were K103N (2%), Y188L (2%), K101E (2%), and V106A (2%), while E138A (2%) was observed according to IAS-USA only. Y115F and M184V (mutations that confer resistance to NRTIs) dual mutations were detected according to both criteria in a single study participant (2%). PDR mutation to protease inhibitors was found to be low (only G73S; 2% according to the CPR tool). Phylogenetic analysis showed that 98% (50/51) of the study participants were infected with HIV-1C virus while one individual (2%) was infected with HIV-1A1 virus. Conclusions This study showed an increased level of PDR and persistence HIV-1C clade homogeneity after 15 years of the rollout of ART and 3 decades of HIV-1C circulation in Ethiopia, respectively. Therefore, we recommend routine baseline genotypic drug resistance testing for all newly diagnosed HIV infected patients before initiating treatment. This will aid the selection of appropriate therapy in achieving the 90% of patients having an undetectable viral load in consonance with the UN target.

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“…Five of those PR1 mutations (Q7K, L33I, L63I, C67A, and C95A) correspond to experimental mutations introduced to minimize autoproteolysis and to prevent cysteine-thiol oxidation of PR1 (Rosé, Salto, & Craikl, 1993). The three remaining PR1 mutations (K14R, S37N, and R41K) correspond to natural polymorphism mutations that were observed in HIV-1 strains isolated from treatmentnaïve and PI-experienced patients (Shaw et al, 2016;Descamps et al, 2009;Azam, Malik, A c c e p t e d M a n u s c r i p t the PR2 sequence set. This position has been reported as polymorphic with the mutation K57R (Damond et al, 2005).…”

Section: -Results and Discussionmentioning

confidence: 95%

Exploration of the effects of sequence variations between HIV-1 and HIV-2 proteases on their three-dimensional structures

Triki

Kermarrec

Visseaux

et al. 2019

Journal of Biomolecular Structure and Dynamics

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HIV protease inhibitors (PIs) approved by the FDA (US Food and Drug Administration) are a major class of antiretroviral. HIV-2 protease (PR2) is naturally resistant to most of them as PIs were designed for HIV-1 protease (PR1). In this study, we explored the impact of amino-acid substitutions between PR1 and PR2 on the structure of protease (PR) by comparing the structural variability of 13 PR regions using 24 PR1 and PR2 structures complexed with diverse ligands. Our analyses confirmed structural rigidity of the catalytic region and highlighted the important role of three regions in the conservation of the catalytic region conformation. Surprisingly, we showed that the flap region, corresponding to a flexible region, exhibits similar conformations in PR1 and PR2. Furthermore, we identified regions exhibiting different conformations in PR1 and PR2, which could be explained by the intrinsic flexibility of these regions, by crystal packing, or by PR1 and PR2 substitutions. Some substitutions induce structural changes in the R2 and R4 regions that could have an impact on the properties of the PI-binding site and could thus modify PI binding mode. Substitutions involved in structural changes in the elbow region could alter the flexibility of the PR2 flap regions relative to PR1, and thus play a role in the transition from the semi-open form to the closed form, and have an impact on ligand binding. These results improve the understanding of the impact of sequence variations between PR1 and PR2 on the natural resistance of HIV-2 to commercially available PIs.

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Zero prevalence of primary drug resistance-associated mutations to protease inhibitors in HIV-1 drug-naive patients in and around Aligarh, India

Cited by 8 publications

References 22 publications

Polymorphisms in HIV-1 Subtype C Reverse Transcriptase and Protease Genes in a Patient Cohort from Mumbai

Polymorphisms in HIV-1 Subtype C Reverse Transcriptase and Protease Genes in a Patient Cohort from Mumbai

Increased HIV-1 pretreatment drug resistance with consistent clade homogeneity among ART-naive HIV-1 infected individuals in Ethiopia

Exploration of the effects of sequence variations between HIV-1 and HIV-2 proteases on their three-dimensional structures

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