title: Prediction of drug-resistance in HIV-1 subtype C based on protease sequences from ART naive and first-line treatment failures in North India using genotypic and docking analysis.
abstract: Genotyping reveal emergence of drug resistance (DR)-related mutations in HIV-1 protease (PR) gene in the first-line treatment failure patients as per Stanford DR database. In order to have a subtype C specific prediction model, a three dimensional structure of local wild type C variant is created and the identified mutations were introduced to assess the mutational effects on protease inhibitors (PI) in a homology model. We estimated viral load, CD4 count and conducted DR genotyping in HIV isolates from 129 therapy naive and 20 first-line treatment failure individuals. Several genotypic variations, as compared to subtype B sequence in the Stanford gene database were detected in HIV-1 subtype C isolates from treatment naive individuals. Among these, nine mutations (12S, 15V, 19I, 36I, 41K, 63P, 69K, 89M, 93L) occurred in more than 60% of the isolates and were considered as local wild type for molecular modelling studies. No major mutations were seen in the PR sequences in isolates from treatment-naive individuals, although isolates from two patients had T74S mutation, known to be associated with reduced susceptibility to nelfinavir (NFV) and a combination of M36I, H69K and L89M mutations found in isolates from 77 patients (59.7%), considered to be conferring resistance to tipranavir (TPV) according to ANRS algorithm. Among the first-line treatment failures, an isolate from one patient showed L33F, I47T, M46G, and G48E mutations conferring intermediate resistance to saquinavir (SQV) and lopinavir (LPV). Though the docking energy scores are in agreement with this interpretation for SQV, it, however, indicated these mutations to be causing intermediate to high level resistance to atazanavir (ATV) and tipranavir (TPV) but making it susceptible to LPV. The patient finally responded to a second-line regimen containing 3TC, AZT and LPV with significant viral suppression. All the DR genotyping studies analyse the results using available databases which are all based on subtype B specific sequences. The proposed homology model in this study is unique, as it may predict subtype C specific susceptibility criteria for the available PIs.
authors.affiliation: Department of Immunopathology, Post Graduate Institute of Medical Education & Research, Chandigarh 160012, India.
authors.forename: Jaideep S
authors.initials: JS
authors.lastname: Toor
authors.forename: Aman
authors.initials: A
authors.lastname: Sharma
authors.forename: Rajender
authors.initials: R
authors.lastname: Kumar
authors.forename: Pawan
authors.initials: P
authors.lastname: Gupta
authors.forename: Prabha
authors.initials: P
authors.lastname: Garg
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Arora
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000821:virology*; D016333:HIV Protease / Q000235:genetics* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D055815:Young Adult
chemical_list: D017320:HIV Protease Inhibitors; D050505:Mutant Proteins; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1