Adaptation to Human Populations Is Revealed by Within-Host Polymorphisms in HIV-1 and Hepatitis C Virus

Open Access
Publisher Website
Google Scholar
Abstract
CD8+ cytotoxic T-lymphocytes (CTLs) perform a critical role in the immune control of viral infections, including those caused by human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV). As a result, genetic variation at CTL epitopes is strongly influenced by host-specific selection for either escape from the immune response, or reversion due to the replicative costs of escape mutations in the absence of CTL recognition. Under strong CTL-mediated selection, codon positions within epitopes may immediately “toggle” in response to each host, such that genetic variation in the circulating virus population is shaped by rapid adaptation to immune variation in the host population. However, this hypothesis neglects the substantial genetic variation that accumulates in virus populations within hosts. Here, we evaluate this quantity for a large number of HIV-1– (n ≥ 3,000) and HCV-infected patients (n ≥ 2,600) by screening bulk RT-PCR sequences for sequencing “mixtures” (i.e., ambiguous nucleotides), which act as site-specific markers of genetic variation within each host. We find that nonsynonymous mixtures are abundant and significantly associated with codon positions under host-specific CTL selection, which should deplete within-host variation by driving the fixation of the favored variant. Using a simple model, we demonstrate that this apparently contradictory outcome can be explained by the transmission of unfavorable variants to new hosts before they are removed by selection, which occurs more frequently when selection and transmission occur on similar time scales. Consequently, the circulating virus population is shaped by the transmission rate and the disparity in selection intensities for escape or reversion as much as it is shaped by the immune diversity of the host population, with potentially serious implications for vaccine design. The rapid accumulation of genetic variation in human viruses, such as human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV), enables these pathogens to elude the immune system and forestalls the development of effective vaccines. This variation may be shaped by selection due to host-specific immune responses, such that the total virus population mirrors the immune diversity of the host population. However, the often-neglected viral genetic variation within hosts may also play an important role in shaping variation in the total virus population. We carry out an innovative analysis of bulk HIV-1 and HCV sequences isolated from over 4,000 human patients, exploiting “mixtures” (i.e., ambiguous nucleotides) as a site-specific marker of within-host genetic variation. We find that nonsynonymous mixtures are disproportionately abundant at codon positions under strong host-specific immune selection. Because existing models of virus evolution provide no explanation for this outcome, we have formulated a new model supplemented with stochastic simulations to demonstrate that the rapid transmission of viruses through diverse selective environments creates a positive correlation between nonsynonymous variation within and among hosts.