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

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    Name:
    Adaptation to human populations ...
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    Genre
    Journal Article
    Date
    2007-03-01
    Author
    Poon, AFY
    Kosakovsky Pond, SL
    Bennett, P
    Richman, DD
    Leigh Brown, AJ
    Frost, SDW
    Subject
    Adaptation, Biological
    CD8-Positive T-Lymphocytes
    Epitopes, T-Lymphocyte
    HIV Infections
    HIV-1
    Hepacivirus
    Hepatitis C
    Humans
    Models, Biological
    Models, Theoretical
    Molecular Sequence Data
    Polymorphism, Genetic
    Reverse Transcriptase Polymerase Chain Reaction
    Stochastic Processes
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    Permanent link to this record
    http://hdl.handle.net/20.500.12613/5625
    
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    DOI
    10.1371/journal.ppat.0030045
    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.
    Citation to related work
    Public Library of Science (PLoS)
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    PLoS Pathogens
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    ae974a485f413a2113503eed53cd6c53
    http://dx.doi.org/10.34944/dspace/5607
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