Loss and Recovery of Genetic Diversity in Adapting Populations of HIV

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.

Author Summary

It is well known that HIV can evolve to become drug resistant if it acquires specific drug-resistance mutations, but the underlying population genetic processes are not well understood. We found that the evolution of drug resistance in HIV populations within infected patients occurs by one mutation at a time (as opposed to multiple mutations simultaneously) and involves both hard and soft sweeps. In a hard sweep, a mutation originates in a single viral particle and then spreads to the entire viral population within the patient. As this mutation increases in frequency, other mutations linked to it hitchhike to high frequencies, which greatly reduces genetic diversity in the population. In a soft sweep, on the other hand, the same resistance mutation originates multiple times on different genetic backgrounds, and hitchhiking may have very little or no effect on diversity. The fact that drug resistance evolves by means of both hard and soft sweeps implies that the HIV populations are limited by the supply of resistance mutations. Using the frequency of hard and soft sweeps we obtain a point estimate of 150,000 for the effective population size of the virus, a number that is much higher than estimates based on diversity at neutral (synonymous) sites, but much lower than the actual number of HIV infected cells in a human patient.