Population genetics of human immunodeficiency virus type 1 during within-host chronic infection
Human immunodeficiency virus type 1 (HIV-1) has high replication and mutation rates that generate large census populations and high levels of genetic variation. Furthermore, there is now widespread global circulation of HIV-1 strains that are recognized to be recombinants of preexisting strains. To elucidate the roles natural selection, population growth, random genetic drift, and recombination have in shaping HIV-1 genetic variation, statistical tests of neutrality were used to analyze up to one-third of the viral genome. Molecular sequences were derived from 145 blood samples from nine men chronically infected with HIV-1 subtype B. These samples were obtained during clinical visits that reflect up to 13.7 years of post-seroconversion infection. At the level of single source infection, recombination was found to occur at a rate between 1.9 x 10-5 and 2.6 x 10 -5 per adjacent sites per generation, approximately equal to the reported mutation rate of 2.5 x 10-5 per site per generation. This rate was found to be highly consistent across both individuals and loci. Episodic evidence for either positive or negative selection was found in 40 samples representing eight of the nine individuals. Methods for distinguishing among recombination, population growth, and natural selection when they have similar effects on phylogenetic or population genetic measures are discussed, as are the false positive consequences of misidentifying the action of these evolutionary forces. Through the use of population-scaled mutation and recombination rates, simulations can be performed that permit generation of appropriate null distributions corresponding to neutral expectations in the presence of recombination, thereby allowing for a more accurate estimation of natural selection. Viral effective population sizes in all nine individuals were found to be consistently on the order of 103, several orders of magnitude lower than census population sizes. A correction is proposed for previous estimates of the viral effective population size of 10 5. The findings imply a predominant role for random genetic drift, a secondary role for natural selection, which was frequently masked by recombination, and no detectable role for population growth, in the evolution of different loci of this highly variable pathogen during chronic infection.
- Microbiology