Abstract
IntroductionHuman APOBEC3G/F (hA3G/F) restricts retroviral replication through G-to-A hypermutations, which can generate drug-resistant progenies in vitro. The clinical relevance is still inconclusive. To bridge this gap, we aim to study the role of these hypermutations in evolution of drug resistance; we characterised hA3G/F-mediated hypermutations in the RT region of the pol gene of patients with or without antiretroviral therapy (ART).MethodsIn 88 HIV-1-positive individuals, drug resistance genotyping was carried out in plasma virus and provirus by population sequencing. Hypermutations were determined by three different approaches using Hypermut 2.0 software, cluster analysis and APOBEC3G-mediated defectives indices. Clinical and demographic characteristics of these individuals were studied in relation to these hypermutations.ResultshA3G/F-mediated hypermutated sequences in proviral DNA, but not in plasma virus, were identified in 11.4% (10/88) subjects. Proviral hypermutations were observed more frequently in patients with ART failure than in ART-naïve individuals (p=0.03). In therapy failure patients, proviral hypermutation were associated with greater intra-compartmental genetic diversity (p<0.001). In therapy-naïve individuals, hypermutated proviral DNA with M184I and M230I mutations due to the editing of hA3G, had stop codons in the open reading frames and the same mutations were absent in the plasma virus. Only a limited concordance was found between the drug resistance mutations in plasma RNA and proviral DNA.ConclusionshA3G lethal hypermutation was significantly associated with ART failure in Indian HIV-1 subtype C patients. It is unlikely that viral variants, which exhibit hypermutated sequences and M184I and/or M230I, will mature and expand in vivo.
Highlights
Human APOBEC3G/F restricts retroviral replication through G-to-A hypermutations, which can generate drug-resistant progenies in vitro
The presence of drug resistance mutations like M184V, T215Y, K103N, and Y181C in plasma virus but not in the provirus in our study indicates that routine HIV RNA monitoring every six months and subsequent plasma viral genotyping at failure identifies the most recent viral populations circulating, different sources of the two viral populations cannot be excluded
Our study showed for the first time that hA3G lethal-hypermutation was associated with the use of treatment in Indian patients who failed antiretroviral therapy (ART)
Summary
Human APOBEC3G/F (hA3G/F) restricts retroviral replication through G-to-A hypermutations, which can generate drug-resistant progenies in vitro. To bridge this gap, we aim to study the role of these hypermutations in evolution of drug resistance; we characterised hA3G/F-mediated hypermutations in the RT region of the pol gene of patients with or without antiretroviral therapy (ART). In therapy-naıve individuals, hypermutated proviral DNA with M184I and M230I mutations due to the editing of hA3G, had stop codons in the open reading frames and the same mutations were absent in the plasma virus. Most of the previous in vivo studies used HIV-1 genes gag, env, vpu, and vif to identify hA3G induced hypermutations in proviral sequences [11Á13]. A few studies have analysed the HIV-1 pol gene, which is a major target in antiretroviral therapy (ART) [14Á16]
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