Genetics, Vol. 166, 1155-1164, March 2004, Copyright © 2004

Influence of Random Genetic Drift on Human Immunodeficiency Virus Type 1 env Evolution During Chronic Infection

Daniel Shrinera, Raj Shankarappaa, Mark A. Jensena, David C. Nicklea, John E. Mittlera, Joseph B. Margolickc, and James I. Mullinsa,b
a Department of Microbiology, University of Washington School of Medicine, Seattle, Washington 98195-8070
b Departments of Medicine and Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington 98195-8070
c Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205

Corresponding author: James I. Mullins, University of Washington School of Medicine, Box 358070, Seattle, WA 98195-8070., jmullins{at}u.washington.edu (E-mail)

Communicating editor: D. CHARLESWORTH

Human immunodeficiency virus type 1 (HIV-1) has high replication and mutation rates that generate large census populations and high levels of genetic variation. We examined the roles of natural selection, population growth, random genetic drift, and recombination in shaping the variation in 1509 C2–V5 env sequences derived from nine men with chronic HIV-1 infection. These sequences were obtained from clinical visits that reflect the first 6–13.7 years of infection. Pairwise comparisons of nonsynonymous and synonymous distances, Tajima's D test, Fu and Li's D* test, and a test of recurrent mutation revealed evidence for episodes of nonneutral evolution in a total of 22 out of 145 blood samples, representing six of the nine individuals. Using three coalescent-based maximum-likelihood estimators, we found viral effective population sizes in all nine individuals to be ~103. We also show that a previous estimate of the effective population size of ~105 based on rare haplotype frequencies decreases to ~103 upon correcting a biased sampling procedure. We conclude that the genetic variation in these data sets can be explained by a predominance of random genetic drift of neutral mutations with brief episodes of natural selection that were frequently masked by recombination.




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