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dc.creatorPoon, AFY
dc.creatorKosakovsky Pond, SL
dc.creatorBennett, P
dc.creatorRichman, DD
dc.creatorLeigh Brown, AJ
dc.creatorFrost, SDW
dc.date.accessioned2021-02-01T22:11:34Z
dc.date.available2021-02-01T22:11:34Z
dc.date.issued2007-03-01
dc.identifier.issn1553-7366
dc.identifier.issn1553-7374
dc.identifier.doihttp://dx.doi.org/10.34944/dspace/5607
dc.identifier.other17397261 (pubmed)
dc.identifier.urihttp://hdl.handle.net/20.500.12613/5625
dc.description.abstractCD8+ 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.
dc.format.extente45-e45
dc.language.isoen
dc.relation.haspartPLoS Pathogens
dc.relation.isreferencedbyPublic Library of Science (PLoS)
dc.subjectAdaptation, Biological
dc.subjectCD8-Positive T-Lymphocytes
dc.subjectEpitopes, T-Lymphocyte
dc.subjectHIV Infections
dc.subjectHIV-1
dc.subjectHepacivirus
dc.subjectHepatitis C
dc.subjectHumans
dc.subjectModels, Biological
dc.subjectModels, Theoretical
dc.subjectMolecular Sequence Data
dc.subjectPolymorphism, Genetic
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectStochastic Processes
dc.titleAdaptation to human populations is revealed by within-host polymorphisms in HIV-1 and hepatitis C virus
dc.typeArticle
dc.type.genreJournal Article
dc.relation.doi10.1371/journal.ppat.0030045
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.creator.orcidPond, Sergei L. Kosakovsky|0000-0003-4817-4029
dc.date.updated2021-02-01T22:11:31Z
refterms.dateFOA2021-02-01T22:11:35Z


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