title: Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals.
abstract: BACKGROUND
  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.
authors: Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. ujjwal.neogi@ki.se
authors: Ujjwal
authors: U
authors: Neogi
authors: Anita
authors: A
authors: Shet
authors: Pravat Nalini
authors: PN
authors: Sahoo
authors: Irene
authors: I
authors: Bontell
authors: Maria L
authors: ML
authors: Ekstrand
authors: Akhil C
authors: AC
authors: Banerjea
authors: Anders
authors: A
authors: Sonnerborg
mesh_terms: D000071480:APOBEC-3G Deaminase; D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D003564:Cytidine Deaminase / Q000276:immunology*; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007194:India; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: D044966:Anti-Retroviral Agents; D004279:DNA, Viral; D012367:RNA, Viral; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase
keywords: APOBEC3G/F; India; antiretroviral therapy; drug resistance; hypermutation