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Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds
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 pa...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370492/ https://www.ncbi.nlm.nih.gov/pubmed/25798934 http://dx.doi.org/10.1371/journal.ppat.1004722 |
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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. |
author_facet | 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. |
author_sort | Yang, Wan-Lin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4370492 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-43704922015-04-04 Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds 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. PLoS Pathog Research Article 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. Public Library of Science 2015-03-23 /pmc/articles/PMC4370492/ /pubmed/25798934 http://dx.doi.org/10.1371/journal.ppat.1004722 Text en © 2015 Yang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article 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. Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds |
title | Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds |
title_full | Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds |
title_fullStr | Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds |
title_full_unstemmed | Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds |
title_short | Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds |
title_sort | persistence of transmitted hiv-1 drug resistance mutations associated with fitness costs and viral genetic backgrounds |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370492/ https://www.ncbi.nlm.nih.gov/pubmed/25798934 http://dx.doi.org/10.1371/journal.ppat.1004722 |
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