Adaptation in the env gene of HIV-1 and evolutionary theories of disease progression

Abstract

The exact mechanisms by which HIV overwhelms the immune system remain poorly understood. Among the several explanations of HIV disease progression, most include adaptation of the viral genome to the host environment as a causal factor. Therefore, quantifying the rate and pattern of adaptive evolution within infected patients is critical to understanding the development of AIDS. Using sequence data from infected individuals sampled at multiple time points, I estimate the within-host adaptation rate of the HIV-1 env gene for viral populations from 50 different patients. I find that, averaging across patients, one adaptive substitution occurs every 3.3 months. Also, one adaptive mutation is driven to a high frequency (>50% but <100%) every 2.5 months. Taken together, such adaptive events occur once every 25 viral generations, which is the fastest adaptation rate ever recorded for a single protein-coding gene. Within the entire env gene, I estimate that a majority (∼55%) of both nonsynonymous substitutions and high-frequency polymorphisms are adaptive. Further, in the C2-V5 region of env, I find that patients with longer asymptomatic periods have virus populations with higher adaptation rates, corroborating the notion that a broad, strong immune response against epitopes in the env gene product leads to longer asymptomatic periods. I conclude by discussing the distribution of non-synonymous changes over the env gene.