Contribution of APOBEC3G/F activity to the development of low-abundance drug-resistant human immunodeficiency virus type 1 variants.
Plasma drug-resistant minority human immunodeficiency virus type 1 variants (DRMVs) increase the risk of virological failure to first-line non-nucleoside reverse transcriptase inhibitor antiretroviral therapy (ART). The origin of DRMVs in ART-naive patients, however, remains unclear. In a large pan-European case-control study investigating the clinical relevance of pre-existing DRMVs using 454 pyrosequencing, the six most prevalent plasma DRMVs detected corresponded to G-to-A nucleotide mutations (V90I, V106I, V108I, E138K, M184I and M230I). Here, we evaluated if such DRMVs could have emerged from apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3G/F (APOBEC3G/F) activity. Out of 236 ART-naive subjects evaluated, APOBEC3G/F hypermutation signatures were detected in plasma viruses of 14 (5.9%) individuals. Samples with minority E138K, M184I, and M230I mutations, but not those with V90I, V106I or V108I, were significantly associated with APOBEC3G/F activity (Fisher's P < 0.005), defined as the presence of > 0.5% of sample sequences with an APOBEC3G/F signature. Mutations E138K, M184I and M230I co-occurred in the same sequence as APOBEC3G/F signatures in 3/9 (33%), 5/11 (45%) and 4/8 (50%) of samples, respectively; such linkage was not found for V90I, V106I or V108I. In-frame STOP codons were observed in 1.5% of all clonal sequences; 14.8% of them co-occurred with APOBEC3G/F signatures. APOBEC3G/F-associated E138K, M184I and M230I appeared within clonal sequences containing in-frame STOP codons in 2/3 (66%), 5/5 (100%) and 4/4 (100%) of the samples. In a re-analysis of the parent case control study, the presence of APOBEC3G/F signatures was not associated with virological failure. In conclusion, the contribution of APOBEC3G/F editing to the development of DRMVs is very limited and does not affect the efficacy of non-nucleoside reverse transcriptase inhibitor ART.
Institut de Recerca de la SIDA IrsiCaixa i Unitat VIH, Universitat Autònoma de Barcelona, Universitat de Vic, Catalonia, Spain. Electronic address: mnoguera@irsicaixa.es.
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M
Noguera-Julian
University College London, London, UK.
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A
Cozzi-Lepri
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
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F
Di Giallonardo
Department of Virology, University Medical Centre, Utrecht, The Netherlands.
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R
Schuurman
Institut für Immunologie und Genetik, Kaiserslautern, Germany.
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M
Däumer
Department of Virology, University Medical Centre, Utrecht, The Netherlands.
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S
Aitken
Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
F
F
Ceccherini-Silberstein
Department of Health Sciences, Clinic of Infectious Diseases, 'San Paolo' Hospital, University of Milan, Milan, Italy.
A
A
D'Arminio Monforte
Institute of Infection & Global Health, University of Liverpool, Liverpool, UK.
A M
AM
Geretti
Department of Virology, Royal Free London NHS Foundation Trust, London, UK.
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CL
Booth
Institute of Virology, University of Cologne, Cologne, Germany.
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R
Kaiser
Competence Network for HIV/AIDS, Bochum, Germany; Clinic for Dermatology, Venereology and Allergology of the Ruhr-Universität, Bochum, Germany; Clinical Trial Centre (ZKS), University Cologne, Germany.
C
C
Michalik
Competence Network for HIV/AIDS, Bochum, Germany; Clinic for Dermatology, Venereology and Allergology of the Ruhr-Universität, Bochum, Germany.
K
K
Jansen
Laboratoire de Virologie, CHU de Bordeaux and MFP-UMR5234, Universite Bordeaux 2, Bordeaux, France.
B
B
Masquelier
Laboratoire de Virologie, CHU de Bordeaux and MFP-UMR5234, Universite Bordeaux 2, Bordeaux, France.
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P
Bellecave
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
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RD
Kouyos
Addiction Medicine, Service of Community Psychiatry, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
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E
Castro
Department of Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland.
H
H
Furrer
University College London, London, UK.
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A
Schultze
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
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HF
Günthard
Department of Virology, Bichat University Hospital, Paris7, France.
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F
Brun-Vezinet
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
K J
KJ
Metzner
Institut de Recerca de la SIDA IrsiCaixa i Unitat VIH, Universitat Autònoma de Barcelona, Universitat de Vic, Catalonia, Spain.
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Paredes
D000071480:APOBEC-3G Deaminase; D023241:Antiretroviral Therapy, Highly Active; D016022:Case-Control Studies; D003564:Cytidine Deaminase / Q000235:genetics*; D043525:Cytosine Deaminase / Q000235:genetics*; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D017393:RNA Editing; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use
D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; C492906:APOBEC3F protein, human; D043525:Cytosine Deaminase; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase
APOBEC3; NNRTI resistance; human immunodeficiency virus type 1; minority variants; resistance