Contribution of APOBEC3G/F activity to the development of low-abundance drug-resistant human immunodeficiency virus type 1 variants

M. Noguera-Julian, A. Cozzi-Lepri, F. Di Giallonardo, R. Schuurman, M. Däumer, S. Aitken, F. Ceccherini-Silberstein, A. D'Arminio Monforte, A. M. Geretti, C. L. Booth, R. Kaiser, C. Michalik, K. Jansen, B. Masquelier, P. Bellecave, R. D. Kouyos, E. Castro, H. Furrer, A. Schultze, H. F. GünthardF. Brun-Vezinet, K. J. Metzner, R. Paredes, Roger Paredes, Karin J. Metzner, A. Cozzi-Lepri, Rob Schuurman, Francoise Brun-Vezinet, Huldrych Günthard, Francesca Ceccherini-Silberstein, Rolf Kaiser, A. M. Geretti, Norbert Brockmeyer, Bernard Masquelier

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    17 Citations (Scopus)

    Abstract

    © 2015 European Society of Clinical Microbiology and Infectious Diseases. 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.
    Original languageEnglish
    Pages (from-to)191-200
    JournalClinical Microbiology and Infection
    Volume22
    Issue number2
    DOIs
    Publication statusPublished - 1 Feb 2016

    Keywords

    • APOBEC3
    • Human immunodeficiency virus type 1
    • Minority variants
    • NNRTI resistance
    • Resistance

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