Rapid Reversion of Sequence Polymorphisms Dominates Early Human Immunodeficiency Virus Type 1 Evolution

Abstract

The error-prone replication of human immunodeficiency virus type 1 (HIV-1) enables it to continuously evade host CD8⁺ T-cell responses. The observed transmission, and potential accumulation, of CD8⁺ T-cell escape mutations in the population may suggest a gradual adaptation of HIV-1 to immune pressures. Recent reports, however, have highlighted the propensity of some escape mutations to revert upon transmission to a new host in order to restore efficient replication capacity. To more specifically address the role of reversions in early HIV-1 evolution, we examined sequence polymorphisms arising across the HIV-1 genome in seven subjects followed longitudinally 1 year from primary infection. As expected, numerous nonsynonymous mutations were associated with described CD8⁺ T-cell epitopes, supporting a prominent role for cellular immune responses in driving early HIV-1 evolution. Strikingly, however, a substantial proportion of substitutions (42%) reverted toward the clade B consensus sequence, with nearly one-quarter of them located within defined CD8 epitopes not restricted by the contemporary host9s HLA. More importantly, these reversions arose significantly faster than forward mutations, with the most rapidly reverting mutations preferentially arising within structurally conserved residues. These data suggest that many transmitted mutations likely incur a fitness cost that is recovered through retrieval of an optimal, or ancestral, form of the virus. The propensity of mutations to revert may limit the accumulation of immune pressure-driven mutations in the population, thus preserving critical CD8⁺ T-cell epitopes as vaccine targets, and argue against an unremitting adaptation of HIV-1 to host immune pressures.