Adaptation to human populations is revealed by within-host polymorphisms in HIV-1 and hepatitis C virus

被引:46
作者
Poon, Art F. Y. [1 ]
Pond, Sergei L. Kosakovsky
Bennett, Phil
Richman, Douglas D.
Brown, Andrew J. Leigh
Frost, Simon D. W.
机构
[1] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA
[2] Univ Warwick, Coventry CV4 7AL, W Midlands, England
[3] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA
[4] Vet Affairs San Diego Healthcare Syt, San Diego, CA USA
[5] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH8 9YL, Midlothian, Scotland
关键词
D O I
10.1371/journal.ppat.0030045
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
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页数:9
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