  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 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 * 10^5
(95% confidence interval 0.8 * 10^5, 4.8 * 10^5). 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.
