Predictable patterns of CTL escape and reversion and the limited role of epistasis in HIV-1 evolution

Predictable patterns of CTL escape and reversion and the limited role of epistasis in HIV-1 evolution
Duncan S. Palmer, Emily Adland, John A. Frater, Philip J.R. Goulder, Kuan-Hsiang Gary Huang, Thumbi Ndung’u, Philippa C. Matthews, Rodney E. Phillips, Roger Shapiro, Gil McVean, Angela R. McLean
Subjects: Populations and Evolution (q-bio.PE)

The twin processes of viral evolutionary escape and reversion in response to host immune pressure, in particular the cytotoxic T-lymphocyte (CTL) response, helps shape Human Immunodeficiency Virus-1 sequence evolution in infected host populations. The tempo of CTL escape and reversion is known to differ between CTL escape variants in a given host population. A wealth of epistatic effects – both intermediary sequence changes on the path to CTL escape and compensatory mutations which restore replicative capacity following viral escape – have been reported. Given the importance of epistatic effects in these processes, we ask: are rates of escape and reversion comparable across infected host populations? For three cohorts taken from three continents, we estimate escape and reversion rates at 23 escape sites in $gag$ epitopes. Surprisingly, we find highly consistent escape rate estimates across the examined cohorts. Reversion rates are also consistent between a Canadian and South African infected host population. We investigate the importance of epistasis further by examining $in$ $vitro$ replicative capacities of viral sequences with minimal variation: point escape mutants induced in a lab strain. Remarkably, despite the complexities of epistatic effects and the diversity of both hosts and viruses, CTL escape mutants which escape rapidly tend to be those with the highest replicative capacity when applied as a single point mutation. Similarly, mutants inducing the greatest costs to viral replicative capacity tend to revert more quickly. These data suggest that escape rates in $gag$ are consistent across host populations and, in general, epistatic effects do not dramatically affect escape rates.


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