Evolution of lamivudine resistance in human immunodeficiency virus type 1-infected individuals: the relative roles of drift and selection

Human immunodeficiency virus type 1 (HIV-1) rapidly develops resistance to lamivudine during monotherapy, typically resulting in the appearance at pos ition 184 in reverse transcriptase (RT) of isoleucine instead of the wild-t ype methionine (M184I) early in therapy, which is later replaced by valine (M184V). M184V reduces viral susceptibility to drug in vitro by approximate ly 100-fold, but also results in a lower processivity of RT. We show that a drop in absolute viral fitness associated with the outgrowth of M184V resu lts in a drop in viral load only in individuals with high CD4(+) counts, fr om whom we estimate the relative fitness of M184V in the presence of drug t o be approximately 10% of that of the wild type prior to therapy. The timin g of emergence of the M184V mutant varies widely between infected individua ls. From analysis of the frequency of M184I and M184V mutants determined at multiple time points in seven individuals during lamivudine therapy, we es timated the fitness advantage of M184V over M184I during therapy to be appr oximately 23% on average. We have also estimated the average ratio of the f requencies of the two mutants prior to therapy to be 0.2:1, with a range fr om 0.12:1 to 0.33:1. We have found that the differences between individuals in the rate of evolution of lamivudine resistance arise due to genetic dri ft affecting the relative frequency of M184I and M184V prior to therapy. Th ese results show that stochastic effects can be significant In HIV evolutio n, even when there is large fitness difference between mutant and wild-type variants.