Intrapatient HIV-1 evolution is dominated by selection on the protein level
in the arms race with the adaptive immune system. When cytotoxic CD8+ T-cells
or neutralizing antibodies target a new epitope, the virus often escapes via
nonsynonymous mutations that impair recognition. Synonymous mutations do not
affect this interplay and are often assumed to be neutral. We analyze
longitudinal intrapatient data from the C2-V5 part of the envelope gene (env)
and observe that synonymous derived alleles rarely fix even though they often
reach high frequencies in the viral population. We find that synonymous
mutations that disrupt base pairs in RNA stems flanking the variable loops of
gp120 are more likely to be lost than other synonymous changes, hinting at a
direct fitness effect of these stem-loop structures in the HIV-1 RNA.
Computational modeling indicates that these synonymous mutations have a
(Malthusian) selection coefficient of the order of -0.002 and that they are
brought up to high frequency by hitchhiking on neighboring beneficial
nonsynonymous alleles. The patterns of fixation of nonsynonymous mutations
estimated from the longitudinal data and comparisons with computer models
suggest that escape mutations in C2-V5 are only transiently beneficial, either
because the immune system is catching up or because of competition between
equivalent escapes