Abstract

The evolution of drug resistance in HIV occurs by the fixation of specific, well-known, drug-resistance mutations, but the underlying population genetic processes are not well understood. By analyzing within-patient longitudinal sequence data, we make four observations that shed a light on the underlying processes and allow us to infer the short-term effective population size of the viral population in a patient. Our first observation is that the evolution of drug resistance usually occurs by the fixation of one drug-resistance mutation at a time, as opposed to several changes simultaneously. Second, we find that these fixation events are accompanied by a reduction in genetic diversity in the region surrounding the fixed drug-resistance mutation, due to the hitchhiking effect. Third, we observe that the fixation of drug-resistance mutations involves both hard and soft selective sweeps. In a hard sweep, a resistance mutation arises in a single viral particle and drives all linked mutations with it when it spreads in the viral population, which dramatically reduces genetic diversity. On the other hand, in a soft sweep, a resistance mutation occurs multiple times on different genetic backgrounds, and the reduction of diversity is weak. Using the frequency of occurrence of hard and soft sweeps we estimate the effective population size of HIV to be ( confidence interval ). This number is much lower than the actual number of infected cells, but much larger than previous population size estimates based on synonymous diversity. We propose several explanations for the observed discrepancies. Finally, our fourth observation is that genetic diversity at non-synonymous sites recovers to its pre-fixation value within 18 months, whereas diversity at synonymous sites remains depressed after this time period. These results improve our understanding of HIV evolution and have potential implications for treatment strategies.

Highlights

  • Understanding the process of adaptation is one of the basic questions in evolutionary biology

  • Selective sweeps reduce genetic diversity We study how the genetic composition of HIV populations in patients treated with a combination of reverse transcriptase (RT) and protease inhibitors changed over the course of about one year

  • We observe soft and hard sweeps in HIV, which leads to an estimated effective population size relevant for adaptation of around 1:5|105

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Summary

Introduction

Understanding the process of adaptation is one of the basic questions in evolutionary biology. In the classical model of adaptation, a beneficial mutation arises once in a single individual and, as this mutation increases in frequency in the population, other mutations ‘‘hitchhike’’ with it to high frequency [3]. In this process, referred to as a ‘‘hard selective sweep’’, genetic diversity at linked sites is strongly reduced when the beneficial mutation fixes in the population. Multiple beneficial alleles may replace the wildtype without leading to a significant reduction in diversity This is called a ‘‘soft selective sweep’’ [4]

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