Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals

Ujjwal Neogi, Anita Shet, Pravat Nalini Sahoo, Irene Bontell, Maria L. Ekstrand, Akhil C. Banerjea, Anders Sonnerborg

Research output: Contribution to journalArticle

Abstract

Introduction: Human 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). Methods: In 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. Results: hA3G/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. Conclusions: hA3G 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.

Original languageEnglish (US)
Article number18472
JournalJournal of the International AIDS Society
Volume16
DOIs
StatePublished - Feb 25 2013
Externally publishedYes

Fingerprint

HIV-1
Drug Resistance
Viruses
Mutation
DNA
Therapeutics
pol Genes
Proviruses
Terminator Codon
Open Reading Frames
Cluster Analysis
human APOBEC3G protein
Software
Demography
RNA
Pharmaceutical Preparations
Population

Keywords

  • Antiretroviral therapy
  • APOBEC3G/F
  • Drug resistance
  • Hypermutation
  • India

ASJC Scopus subject areas

  • Infectious Diseases
  • Public Health, Environmental and Occupational Health

Cite this

Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals. / Neogi, Ujjwal; Shet, Anita; Sahoo, Pravat Nalini; Bontell, Irene; Ekstrand, Maria L.; Banerjea, Akhil C.; Sonnerborg, Anders.

In: Journal of the International AIDS Society, Vol. 16, 18472, 25.02.2013.

Research output: Contribution to journalArticle

Neogi, Ujjwal ; Shet, Anita ; Sahoo, Pravat Nalini ; Bontell, Irene ; Ekstrand, Maria L. ; Banerjea, Akhil C. ; Sonnerborg, Anders. / Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals. In: Journal of the International AIDS Society. 2013 ; Vol. 16.
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abstract = "Introduction: Human 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). Methods: In 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. Results: hA3G/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-na{\"i}ve individuals (p = 0.03). In therapy failure patients, proviral hypermutation were associated with greater intra-compartmental genetic diversity (p < 0.001). In therapy-na{\"i}ve 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. Conclusions: hA3G 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.",
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AU - Shet, Anita

AU - Sahoo, Pravat Nalini

AU - Bontell, Irene

AU - Ekstrand, Maria L.

AU - Banerjea, Akhil C.

AU - Sonnerborg, Anders

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AB - Introduction: Human 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). Methods: In 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. Results: hA3G/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. Conclusions: hA3G 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.

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KW - Hypermutation

KW - India

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