Deleterious synonymous mutations hitchhike to high frequency in HIV-1 env evolution

TL;DR

This study reveals that certain synonymous mutations in HIV-1 env can reach high frequency through hitchhiking with beneficial nonsynonymous mutations, challenging the assumption of neutrality for synonymous changes.

Contribution

It demonstrates that synonymous mutations disrupting RNA stem structures can be indirectly selected for via hitchhiking with beneficial mutations in HIV-1 env.

Findings

Synonymous mutations rarely fix but often reach high frequency.

Disruption of RNA stem structures correlates with mutation loss.

Hitchhiking explains high-frequency synonymous mutations.

Abstract

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.