Genetic drift and within-host metapopulation dynamics of HIV-1 infection

Abstract

Most HIV replication occurs in solid lymphoid tissue, which has prominent architecture at the histological level, which separates groups of productively infected CD4 ؉ cells. Nevertheless, current population models of HIV assume panmixis within lymphoid tissue. We present a simple ''metapopulation'' model of HIV replication, where the population of infected cells is comprised of a large number of small populations, each of which is established by a few founder viruses and undergoes turnover. To test this model, we analyzed viral genetic variation of infected cell subpopulations within the spleen and demonstrated the action of founder effects as well as significant variation in the extent of genetic differentiation between subpopulations among patients. The combination of founder effects and subpopulation turnover can result in an effective population size much lower than the actual population size and may contribute to the importance of genetic drift in HIV evolution despite a large number of infected cells.H IV has an enormous evolutionary potential because of the combination of a high mutation rate (Ϸ3 ϫ 10 Ϫ5 substitutions͞site͞generation; ref. 1), a short generation time (Ϸ2.6 days; refs. 2 and 3), and a large number of infected cells within the host (10 7 -10 8 infected cells; ref. 4). Many analyses of the pattern of nucleotide substitution in the viral env gene have detected evolution in response to positive selection (5-16), although relatively few studies have linked these patterns of viral genetic variation to selection by defined immune responses or for changes in viral phenotype associated with coreceptor usage. In the presence of antiretroviral agents that target viral protease and reverse transcriptase, positive selection has been described in numerous studies, which demonstrate convergent evolution in different individuals of mutations that confer drug resistance (17)(18)(19)(20). Although specific mutations have been identified with escape from immune responses and escape from antiretrovirals, viral genetic variation reflects more than just these focused positive selection pressures and may reflect more subtle processes of within-host competition between viruses for higher replicative potential.Despite an enormous potential to respond to selection, there can be substantial differences between infected individuals in the evolution of drug resistance. For example, the frequency of single drug-resistant mutants in viral protease and reverse transcriptase before therapy can vary dramatically between hosts (21-23), apparently by random. Indirect observations of the apparently stochastic way in which multiply resistant mutants emerge during therapy are also consistent with a role of genetic drift (18,24,25). In addition, three studies of the evolution of env gene sequences have found substantially lower genetic variation than expected for a population of the order of 10 7 (24,26,27). These studies estimated the ''effective'' population size to be of the order of 10 3 , reflecting the high relatedness be...

Estimate of effective recombination rate and average selection coefficient for HIV in chronic infection

“…Therefore, the existence of random drift and sampling attributable to finite population size is also a very important factor. A typical infection comprises N ∼ 10 8 infected cells; the effective number, however, is unknown and may be much smaller, although early estimates based on fewsite models suggested at least 10 5 -10 6 infected cells (9,11,12). Analytical models of multisite evolution, both in the presence and absence of recombination, predict that although a finite population size is important, the adaptation rate depends rather weakly (logarithmically) on it (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)40).…”

Cytidine deamination induced HIV-1 drug resistance

“…Comparable high numbers of M184I RT mutants were detected in HIV-1 genomes recovered from resting CD4 ϩ cells of HAART-treated patients (21). HIV-1 sequence diversification is thought to originate from random errors introduced during RT and caused by either the low fidelity of retroviral RT or recombination events (34). Using an amended drug-resistance selection protocol, we demonstrate that viral stocks produced by a mixture of hypermutated and WT genomes have a clear growth advantage over pure WT HIV-1 controls when propagated in the presence of high concentrations of 3TC.…”

Synonymous Substitution Rates Predict HIV Disease Progression as a Result of Underlying Replication Dynamics

“…doi:10.1371/journal.pcbi.0030029.g001 may be because dN rates are determined primarily by the strength of selection on viral mutations, rather than by the absolute rate at which those mutations are generated. Furthermore, most diversifying selection in env results from nAb responses [31], which are not expected to moderate replication rates and disease progression. To demonstrate this, we further analyzed env sequences sampled through time from two patients with markedly distinct rates of phenotypic escape from nAb responses [31] (patient 01-0083 and patient 01-0127; Figure 4).…”

“…Furthermore, most diversifying selection in env results from nAb responses [31], which are not expected to moderate replication rates and disease progression. To demonstrate this, we further analyzed env sequences sampled through time from two patients with markedly distinct rates of phenotypic escape from nAb responses [31] (patient 01-0083 and patient 01-0127; Figure 4). As in Frost et al [2], we show that the virus that rapidly escaped nAb responses in patient 01-0127 accumulated nonsynonymous substitutions at a considerably higher rate on backbone branches, while synonymous divergence rates appear to be unaffected (similar plots were obtained for internal branches, unpublished data).…”