Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease
Name
pgen.1009009.pdf
Description
Published version
Size
2.02 MB
Format
Adobe PDF
Checksum (MD5)
4367cb85e3e16f347299c7a07541dbba
Author(s)
Zhang, Tian-hao
Dai, Lei
Barton, John P
Du, Yushen
Tan, Yuxiang
Pang, Wenwen
Chakraborty, Arup K
Lloyd-Smith, James O
Sun, Ren
Date Issued
2020
Journal
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Version
Final published version
Abstract
Copyright: © 2020 Zhang et al. 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 credited. Drug-resistant mutations often have deleterious impacts on replication fitness, posing a fitness cost that can only be overcome by compensatory mutations. However, the role of fitness cost in the evolution of drug resistance has often been overlooked in clinical studies or in vitro selection experiments, as these observations only capture the outcome of drug selection. In this study, we systematically profile the fitness landscape of resistance-associated sites in HIV-1 protease using deep mutational scanning. We construct a mutant library covering combinations of mutations at 11 sites in HIV-1 protease, all of which are associated with resistance to protease inhibitors in clinic. Using deep sequencing, we quantify the fitness of thousands of HIV-1 protease mutants after multiple cycles of replication in human T cells. Although the majority of resistance-associated mutations have deleterious effects on viral replication, we find that epistasis among resistance-associated mutations is predominantly positive. Furthermore, our fitness data are consistent with genetic interactions inferred directly from HIV sequence data of patients. Fitness valleys formed by strong positive epistasis reduce the likelihood of reversal of drug resistance mutations. Overall, our results support the view that strong compensatory effects are involved in the emergence of clinically observed resistance mutations and provide insights to understanding fitness barriers in the evolution and reversion of drug resistance.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Physics
Massachusetts Institute of Technology. Department of Chemistry
Ragon Institute of MGH, MIT and Harvard
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
10.1371/journal.pgen.1009009
https://doi.org/10.1371/journal.pgen.1009009
