Adaptation to human populations is revealed by within-host polymorphisms in HIV-1 and hepatitis C virus
Genre
Journal ArticleDate
2007-03-01Author
Poon, AFYKosakovsky Pond, SL
Bennett, P
Richman, DD
Leigh Brown, AJ
Frost, SDW
Subject
Adaptation, BiologicalCD8-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
Permanent link to this record
http://hdl.handle.net/20.500.12613/5625
Metadata
Show full item recordDOI
10.1371/journal.ppat.0030045Abstract
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)Has part
PLoS PathogensADA compliance
For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.eduae974a485f413a2113503eed53cd6c53
http://dx.doi.org/10.34944/dspace/5607