Genetic Drift and Within Host Metapopulation Structure in the Evolution of HIV

Simon D. W. Frost and Andrew J. Leigh Brown

The highly variable way in which drug resistance evolves in different HIV-infected individuals has led to the suggestion that HIV evolution may have a strong stochastic component. Genetic drift in the frequency of drug resistant virus prior to therapy can lead to variability between individuals in the rate of evolution of resistance during early therapy. Genetic drift of may also generate variability in the rate of evolution of highly fit resistant virus during ongoing therapy, as these mutants may disappear by chance before they reach a frequency where fixation is effectively certain. The importance of genetic drift can be quantified by determining the variance effective population size, which indicates the amount of noise in gene frequencies over a generation. To indirectly estimate the variance effective population size of HIV within the infected host, we have analysed data on the outgrowth of lamivudine resistant mutants, M184I and M184V in reverse transcriptase, during lamivudine monotherapy. By extrapolating back to the initiation of therapy, we show that there is considerable variation in the relative frequencies of M184I and M184V prior to therapy. Using a simple but robust stochastic model, we show that this variation is consistent with a variance effective population size of a million or less i.e. at least 10-100 times lower than the actual population size. We hypothesised that this difference between the actual and the effective population size may have arisen as a consequence of a metapopulation structure of infected cells within the host, where small subpopulations of infected cells, which are formed by one or a few founders, have a high rate of turnover, due to a limited supply of target cells within subpopulations and the short lifetime of individual infected cells. A low variance effective population size arises as founding infected cells produce more daughter infected cells than those in subpopulations where infection has already been established. To test whether such a metapopulation structure exists within solid tissue, where the majority of viral replication occurs, we have analysed sequence data from the V1/V2 region of the envelope gene obtained from provirus isolated from multiple splenic white pulps taken from six HIV infected individuals and one SIV-infected macaque. We show that the pattern of genetic variation within and between virus isolated from splenic white pulps is consistent with a metapopulation model of colonisation and extinction. Our results show that genetic drift is sufficient to generate significant differences in the evolution of single resistance mutations and that this drift may arise as a consequence of a high turnover of small subpopulations of infected cells.

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