Speaker
Description
It is 20 years since the perplexing observation that HIV evolves around five times faster when measured within, compared to between, hosts. Emergence of CTL- and antibody-escape mutations within individuals, followed by their reversion after transmission, has been proposed to explain the mismatch in evolutionary rates at nonsynonymous sites, but a compelling explanation for the mismatch at synonymous genomic positions has remained elusive. Using data from longitudinally sampled transmission pairs, we provide evidence that toggling of synonymous mutations during the course of infection can explain the mismatch at synonymous positions. Specifically, we observed slightly deleterious synonymous mutations hitchhiking with immune-escape mutations to high frequency, before linkage is lost due to back-mutation or recombination, after which the synonymous mutations decline in frequency. If sampling is sufficiently frequent, these toggles are captured and contribute to high within-host evolutionary rates, whereas the transmitted virus is more likely to consist of founder-like alleles. To support this conclusion, we nested within-host agent-based simulations into between-host transmission networks, which were parameterised using data from the transmission pairs. These simulations confirm that toggling of nonsynonymous mutations between hosts, combined with the hitchhiking of synonymous mutations with these nonsynonymous mutations within-host, is sufficient to explain observed mismatches in evolutionary rates.
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