Abstract
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 conditions.
Highlights
Epistasis, the fitness interaction between mutations, has been suggested to influence the evolutionary dynamics of virus populations [1]
In order to quantify precisely epistatic interactions in human immunodeficiency virus (HIV) and analyze their dependence on environmental factors such as host cells and antiviral drugs, we focused on a specific mutational pathway that human immunodeficiency virus type 1 (HIV-1) follows in vivo during treatment with AZT, the prototypic reverse transcriptase (RT) inhibitor first used in infected patients and a common component of current anti-retroviral formulations
Epistasis is a fundamental component of the genetic architecture of biological entities and has been suggested to influence the evolutionary dynamics of virus populations
Summary
The fitness interaction between mutations, has been suggested to influence the evolutionary dynamics of virus populations [1]. In its original definition by Bateson, epistasis described a phenomenon in which a discrete phenotype derived from a genetic variant in one locus was altered by a genetic variant at another locus [2] Both loci must be located within the same phenotype-determining gene clusters and show some kind of interaction. Fitness interactions can act in different directions If mutations interact such that their combined effect on fitness is greater than expected from their individual effects, epistasis is said to be synergistic. Synergistic interactions result in negative epistasis and antagonistic interactions result in positive epistasis. The contrary is true for beneficial mutations were synergistic interactions result in positive epistasis and antagonistic interactions result in negative epistasis [3,4]
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