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Epidemiological and Biological Evidence for a Compensatory Effect of Connection Domain Mutation N348I on M184V in HIV-1 Reverse Transcriptase

von Wyl, Viktor ; Ehteshami, Maryam ; Symons, Jori ; Bürgisser, Philippe ; Nijhuis, Monique ; Demeter, Lisa M. ; Yerly, Sabine ; Böni, Jürg ; Klimkait, Thomas ; Schuurman, Rob ; Ledergerber, Bruno ; Götte, Matthias ; Günthard, Huldrych F.

In: The Journal of Infectious Diseases, 2010, vol. 201, no. 7, p. 1054-1062

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    Titel
    • Epidemiological and Biological Evidence for a Compensatory Effect of Connection Domain Mutation N348I on M184V in HIV-1 Reverse Transcriptase
    Autor
    • von Wyl, Viktor. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich
    • Ehteshami, Maryam. Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
    • Symons, Jori. Department of Virology, University Medical Center, Utrecht, the Netherlands
    • Bürgisser, Philippe. Lausanne University Hospital, Lausanne
    • Nijhuis, Monique. Department of Virology, University Medical Center, Utrecht, the Netherlands
    • Demeter, Lisa M.. Infectious Diseases Division, University of Rochester School of Medicine and Dentistry, Rochester, New York
    • Yerly, Sabine. Geneva University Hospital, Geneva
    • Böni, Jürg. Institute of Medical Virology, Swiss National Center for Retroviruses, University of Zurich, Zurich
    • Klimkait, Thomas. University of Basel, Basel, Switzerland
    • Schuurman, Rob. Lausanne University Hospital, Lausanne
    • Ledergerber, Bruno. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich
    • Götte, Matthias. Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
    • Günthard, Huldrych F.. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • The Journal of Infectious Diseases, 2010, vol. 201, no. 7, p. 1054-1062. The University of Chicago Press
    Andere elektronische Ausgabe
    Klassifikation
    • Gesundheit
    OAI-PMH-ID
    • oai:doc.rero.ch:295285
    Summary
    Background. The connection domain mutation N348I confers resistance to zidovudine (AZT) and is associated with the lamivudine (3TC) mutation M184V. We explored the biochemical and virological influence of N348I in the context of M184V. Methods. Genotypic resistance data for patients receiving monotherapy or dual therapy with AZT, lamivudine (3TC), or AZT/3TC were analyzed. Rates of N348I emergence were compared between treatment groups. Mutant reverse transcriptases (RTs) containing M184V and/or N348I were generated to study enzymatic and virological properties. Results. We included 50 AZT-treated, 11 3TC-treated, and 10 AZT/3TC-treated patients. N348I was observed in 3 (6%), 0, and 4 (40%) of these patients, respectively. The rate of N348I emergence was increased by 5-fold in the AZT/3TC group (11.7 instances [95% confidence interval {CI}, 3.2-30.1 instances] per 100 person-years of receipt of AZT), compared with the rate noted for the AZT group (2.3 instances [95% CI, 0.4-6.8 instances] per 100 person-years of receipt of AZT; P = .04). Biochemical data show that N348I can partially compensate for the diminution in processive DNA synthesis and the reduction in AZT excision associated with M184V. Furthermore, virological analyses demonstrate that N348I confers low-level resistance to AZT and partly restores the reduced RT activity of the M184V variant. Conclusion. In vivo selection of N348I is driven by AZT and is further facilitated when 3TC is coadministered. Compensatory interactions between N348I and M184V help to explain these findings