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Persistence of transmitted HIV-1 drug resistance mutations associated with fitness costs and viral genetic backgrounds.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Yang Wan-Lin, Kouyos Roger D, Böni Jürg, Yerly Sabine, Klimkait Thomas, Aubert Vincent, Scherrer Alexandra U, Shilaih Mohaned, Hinkley Trevor, Petropoulos Christos, Bonhoeffer Sebastian, Günthard Huldrych F,
Project Swiss HIV Cohort Study (SHCS)
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Original article (peer-reviewed)

Journal PLoS pathogens
Volume (Issue) 11(3)
Page(s) 1004722 - 1004722
Title of proceedings PLoS pathogens
DOI 10.1371/journal.ppat.1004722

Open Access

URL http://doi.org/10.1371/journal.ppat.1004722
Type of Open Access Publisher (Gold Open Access)

Abstract

Transmission of drug-resistant pathogens presents an almost-universal challenge for fighting infectious diseases. Transmitted drug resistance mutations (TDRM) can persist in the absence of drugs for considerable time. It is generally believed that differential TDRM-persistence is caused, at least partially, by variations in TDRM-fitness-costs. However, in vivo epidemiological evidence for the impact of fitness costs on TDRM-persistence is rare. Here, we studied the persistence of TDRM in HIV-1 using longitudinally-sampled nucleotide sequences from the Swiss-HIV-Cohort-Study (SHCS). All treatment-naïve individuals with TDRM at baseline were included. Persistence of TDRM was quantified via reversion rates (RR) determined with interval-censored survival models. Fitness costs of TDRM were estimated in the genetic background in which they occurred using a previously published and validated machine-learning algorithm (based on in vitro replicative capacities) and were included in the survival models as explanatory variables. In 857 sequential samples from 168 treatment-naïve patients, 17 TDRM were analyzed. RR varied substantially and ranged from 174.0/100-person-years;CI=[51.4, 588.8] (for 184V) to 2.7/100-person-years;[0.7, 10.9] (for 215D). RR increased significantly with fitness cost (increase by 1.6[1.3,2.0] per standard deviation of fitness costs). When subdividing fitness costs into the average fitness cost of a given mutation and the deviation from the average fitness cost of a mutation in a given genetic background, we found that both components were significantly associated with reversion-rates. Our results show that the substantial variations of TDRM persistence in the absence of drugs are associated with fitness-cost differences both among mutations and among different genetic backgrounds for the same mutation.
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