Originally published as Genetics Published Articles Ahead of Print on September 1, 2006.

Genetics, Vol. 174, 1441-1453, November 2006, Copyright © 2006
doi:10.1534/genetics.105.052019

Evolution of the Human Immunodeficiency Virus Envelope Gene Is Dominated by Purifying Selection

C. T. T. Edwards^*,1, E. C. Holmes, O. G. Pybus, D. J. Wilson, R. P. Viscidi^**, E. J. Abrams, R. E. Phillips^* and A. J. Drummond^,2

^* Nuffield Department of Clinical Medicine and Department of Statistics, University of Oxford, Oxford OX1 3SY, United Kingdom, Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, University Park, Pennsylvania 16802, Department of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom, ^** Department of Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland 21287 and Department of Pediatrics, Columbia University College of Physicians and Surgeons and Harlem Hospital Center, New York, New York 10032

¹ Corresponding author: Department of Maths and Applied Maths, University of Cape Town, Rondebosch, Cape Town 7701, Republic of South Africa.
E-mail: cedwards{at}maths.uct.ac.za

The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the rapid, continuous turnover of genetic diversity. However, the role of natural selection, relative to random genetic drift, in governing this process is unclear. We tested a stochastic model of genetic drift using partial envelope sequences sampled longitudinally in 28 infected children. In each case the Bayesian posterior (empirical) distribution of coalescent genealogies was estimated using Markov chain Monte Carlo methods. Posterior predictive simulation was then used to generate a null distribution of genealogies assuming neutrality, with the null and empirical distributions compared using four genealogy-based summary statistics sensitive to nonneutral evolution. Because both null and empirical distributions were generated within a coalescent framework, we were able to explicitly account for the confounding influence of demography. From the distribution of corrected P-values across patients, we conclude that empirical genealogies are more asymmetric than expected if evolution is driven by mutation and genetic drift only, with an excess of low-frequency polymorphisms in the population. This indicates that although drift may still play an important role, natural selection has a strong influence on the evolution of HIV-1 envelope. A negative relationship between effective population size and substitution rate indicates that as the efficacy of selection increases, a smaller proportion of mutations approach fixation in the population. This suggests the presence of deleterious mutations. We therefore conclude that intrahost HIV-1 evolution in envelope is dominated by purifying selection against low-frequency deleterious mutations that do not reach fixation.

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