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A Jung

AMM Nowak

Andreas Meyerhans

Anna Ignatovich

CJ Petropoulos

CL Althaus

CL Burch

CV Fletcher

D Richman

Darren Martin

DV Havlir

EA Ortlund

EJ Arts

EJ Platt

FL Graham

Gennady Bocharov

HC Gelderblom

HJ Cordell

J da Silva

JA de Visser

Javier P. Martínez

JL Badano

Jochen Reiter

JT Slusher

JW Gregersen

K Wang

KA Tsetsarkin

KK Arien

M Parera

M Rolland

Matthias T. Dittmar

N Beerenwinkel

N Sluis-Cremer

O Carlborg

OK Silander

PB Armitage

PL Boyer

PR Harrigan

R Montville

R Sanjuan

RD Kouyos

S Bonhoeffer

S Crotty

S Gavrilets

SF Elena

SF Lacey

Simon Wain-Hobson

SN Ho

SP Otto

T Neumann

T van Opijnen

TW Chun

W Bateson

X Wei

Y Maeda

Y Michalakis

Z Hu

PLoS ONE

English

PubMed

Fitness interactions between mutations, referred to as epistasis, can strongly impact evolution. For RNA viruses and retroviruses with their high mutation rates, epistasis may be particularly important to overcome fitness losses due to the accumulation of deleterious mutations and thus could influence the frequency of mutants in a viral population. As human immunodeficiency virus type 1 (HIV-1) resistance to azidothymidine (AZT) requires selection of sequential mutations, it is a good system to study the impact of epistasis. Here we present a thorough analysis of a classical AZT-resistance pathway (the 41–215 cluster) of HIV-1 variants by fitness measurements in single round infection assays covering physiological drug concentrations ex vivo. The sign and value of epistasis varied and did not predict the epistatic effect on the mutant frequency. This complex behavior is explained by the fitness ranking of the variants that strongly depends on environmental factors, i.e., the presence and absence of drugs and the host cells used. Although some interactions compensate fitness losses, the observed small effect on the relative mutant frequencies suggests that epistasis might be inefficient as a buffering mechanism for fitness losses in vivo. While the use of epistasis-based hypotheses to make general assumptions on the evolutionary dynamics of viral populations is appealing, our data caution their interpretation without further knowledge on the characteristics of the viral mutant spectrum under different environmental conditionsThis work was supported by grants from the Deutsche Forschungsgemeinschaft, the Deutsche Akademische Austauschdienst (DAAD), and the Russian Foundation for Basic  Research  and by the Program of the Russian Academy of Sciences "Basic Research for Medicine". The funders  had no role in study design, data collection and analysis,  decision  to  publish, or preparation  of  the  manuscrip

Martinez, Javier P.

Bocharov, Gennady A.

Ignatovich, Anna

Reiter, Jochen

Dittmar, Matthias T

Wain-Hobson, Simon

Meyerhans, Andreas

UPF Digital Repository

Fitness ranking of individual mutants drives patterns of epistatic interactions in HIV-1

International audienceFitness interactions between mutations, referred to as epistasis, can strongly impact evolution. For RNA viruses and retroviruses with their high mutation rates, epistasis may be particularly important to overcome fitness losses due to the accumulation of deleterious mutations and thus could influence the frequency of mutants in a viral population. As human immunodeficiency virus type 1 (HIV-1) resistance to azidothymidine (AZT) requires selection of sequential mutations, it is a good system to study the impact of epistasis. Here we present a thorough analysis of a classical AZT-resistance pathway (the 41-215 cluster) of HIV-1 variants by fitness measurements in single round infection assays covering physiological drug concentrations ex vivo. The sign and value of epistasis varied and did not predict the epistatic effect on the mutant frequency. This complex behavior is explained by the fitness ranking of the variants that strongly depends on environmental factors, i.e., the presence and absence of drugs and the host cells used. Although some interactions compensate fitness losses, the observed small effect on the relative mutant frequencies suggests that epistasis might be inefficient as a buffering mechanism for fitness losses in vivo. While the use of epistasis-based hypotheses to make general assumptions on the evolutionary dynamics of viral populations is appealing, our data caution their interpretation without further knowledge on the characteristics of the viral mutant spectrum under different environmental conditions

Martínez, Javier P

Bocharov, Gennady

Hal-Diderot

Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1.

Martinez, JP

Bocharov, G

Ignatovich, A

Reiter, J

Dittmar, MT

Wain-Hobson, S

Meyerhans, A

Queen Mary Research Online

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Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1

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https://hal-pasteur.archives-ouvertes.fr/pasteur-00591078/file/journal.pone.0018375.pdf

Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1

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