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 1:5|105 (95% confidence interval ½0:8|105,4:8|105). 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.

Citation: Pennings PS, Kryazhimskiy S, Wakeley J (2014) Loss and Recovery of Genetic Diversity in Adapting Populations of HIV. PLoS Genet 10(1): e1004000.
doi:10.1371/journal.pgen.1004000

Editor: Christophe Fraser, Imperial College London, United Kingdom
Received April 19, 2013; Accepted October 19, 2013; Published January 23, 2014

Copyright: 2014 Pennings 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.

Funding: SK was supported by a Career Award at Scientific Interface from the Burroughs Wellcome Fund (http://www.bwfund.org/). PSP was supported by a
long-term postdoctoral fellowship of the Human Frontier Science Program (http://www.hfsp.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.

* E-mail: pleuni@stanford.edu