title: Persistence of transmitted HIV-1 drug resistance mutations associated with fitness costs and viral genetic backgrounds.
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.
authors: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors: Wan-Lin
authors: WL
authors: Yang
authors: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors: Roger D
authors: RD
authors: Kouyos
authors: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors: Jürg
authors: J
authors: Böni
authors: Laboratory of Virology and AIDS Center, Geneva University Hospital, Geneva, Switzerland.
authors: Sabine
authors: S
authors: Yerly
authors: Department Biomedicine-Petersplatz, University of Basel, Basel, Switzerland.
authors: Thomas
authors: T
authors: Klimkait
authors: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors: Vincent
authors: V
authors: Aubert
authors: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors: Alexandra U
authors: AU
authors: Scherrer
authors: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors: Mohaned
authors: M
authors: Shilaih
authors: Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland.
authors: Trevor
authors: T
authors: Hinkley
authors: Monogram Biosciences, South San Francisco, California, United States of America.
authors: Christos
authors: C
authors: Petropoulos
authors: Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland.
authors: Sebastian
authors: S
authors: Bonhoeffer
authors: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors: Huldrych F
authors: HF
authors: Günthard
mesh_terms: D000328:Adult; D015331:Cohort Studies; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000235:genetics* / Q000635:transmission*; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009154:Mutation