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Role of Gag mutations in PI resistance in the Swiss HIV cohort study: bystanders or contributors?


Kletenkov, K; Hoffmann, D; Böni, J; Yerly, S; Aubert, V; Schöni-Affolter, F; Struck, D; Verheyen, J; Klimkait, T (2017). Role of Gag mutations in PI resistance in the Swiss HIV cohort study: bystanders or contributors? Journal of Antimicrobial Chemotherapy, 72(3):866-875.

Abstract

Background: HIV Gag mutations have been reported to confer PI drug resistance. However, clinical implications are still controversial and most current genotyping algorithms consider solely the protease gene for assessing PI resistance. Objectives: Our goal was to describe for HIV infections in Switzerland the potential role of the C-terminus of Gag (NC–p6) in PI resistance. We aimed to characterize resistance-relevant mutational patterns in Gag and protease and their possible interactions. Methods: Resistance information on plasma samples from 2004–12 was collected for patients treated by two diagnostic centres of the Swiss HIV Cohort Study. Sequence information on protease and the C-terminal Gag region was paired with the corresponding patient treatment history. The prevalence of Gag and protease mutations was analysed for PI treatment-experienced patients versus PI treatment-naive patients. In addition, we modelled multiple paths of an assumed ordered accumulation of genetic changes using random tree mixture models. Results: More than half of all PI treatment-experienced patients in our sample set carried HIV variants with at least one of the known Gag mutations, and 17.9% (66/369) carried at least one Gag mutation for which a phenotypic proof of PI resistance by in vitro mutagenesis has been reported. We were able to identify several novel Gag mutations that are associated with PI exposure and therapy failure. Conclusions: Our analysis confirmed the association of Gag mutations, well known and new, with PI exposure. This could have clinical implications, since the level of potential PI drug resistance might be underestimated.

Abstract

Background: HIV Gag mutations have been reported to confer PI drug resistance. However, clinical implications are still controversial and most current genotyping algorithms consider solely the protease gene for assessing PI resistance. Objectives: Our goal was to describe for HIV infections in Switzerland the potential role of the C-terminus of Gag (NC–p6) in PI resistance. We aimed to characterize resistance-relevant mutational patterns in Gag and protease and their possible interactions. Methods: Resistance information on plasma samples from 2004–12 was collected for patients treated by two diagnostic centres of the Swiss HIV Cohort Study. Sequence information on protease and the C-terminal Gag region was paired with the corresponding patient treatment history. The prevalence of Gag and protease mutations was analysed for PI treatment-experienced patients versus PI treatment-naive patients. In addition, we modelled multiple paths of an assumed ordered accumulation of genetic changes using random tree mixture models. Results: More than half of all PI treatment-experienced patients in our sample set carried HIV variants with at least one of the known Gag mutations, and 17.9% (66/369) carried at least one Gag mutation for which a phenotypic proof of PI resistance by in vitro mutagenesis has been reported. We were able to identify several novel Gag mutations that are associated with PI exposure and therapy failure. Conclusions: Our analysis confirmed the association of Gag mutations, well known and new, with PI exposure. This could have clinical implications, since the level of potential PI drug resistance might be underestimated.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:mutation, swiss hiv cohort study
Language:English
Date:1 March 2017
Deposited On:26 Jan 2017 08:10
Last Modified:02 Apr 2017 01:02
Publisher:Oxford University Press
ISSN:0305-7453
Funders:Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #148522), SHCS project #720, SHCS research foundation, Deutsche Forschungsgemeinschaft, grant TRR60/B1 (for DH), Boehringer Ingelheim (travel grant to KK)
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/jac/dkw493
PubMed ID:27999036

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