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

Abstract

Human immunodeficiency virus type 1 (HIV-1) rapidly develops resistance to lamivudine during monotherapy, typically resulting in the appearance at position 184 in reverse transcriptase (RT) of isoleucine instead of the wild-type methionine (M184I) early in therapy, which is later replaced by valine (M184V). M184V reduces viral susceptibility to drug in vitro by approximately 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 results in a drop in viral load only in individuals with high CD4(+) counts, from whom we estimate the relative fitness of M184V in the presence of drug to be approximately 10% of that of the wild type prior to therapy. The timing of emergence of the M184V mutant varies widely between infected individuals. From analysis of the frequency of M184I and M184V mutants determined at multiple time points in seven individuals during lamivudine therapy, we estimated the fitness advantage of M184V over M184I during therapy to be approximately 23% on average. We have also estimated the average ratio of the frequencies of the two mutants prior to therapy to be 0. 2:1, with a range from 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 drift affecting the relative frequency of M184I and M184V prior to therapy. These results show that stochastic effects can be significant in HIV evolution, even when there is large fitness difference between mutant and wild-type variants.

FIG. 1

Estimates of the percentage of methionine (M [white]), isoleucine (I [gray]), and valine (V [black]) at position 184 of RT after approximately 2, 3, and 4 weeks of 3TC monotherapy.

FIG. 2

Plot of the log ratio of the frequency of the valine to the isoleucine mutants, ln(M184V/M184I), over time in generations, assuming a generation time of 2.6 days for each patient.

FIG. 3

Approximate values for the mean and the CV of the frequency of M184V relative to M184I prior to therapy, p₂(0)/p₁(0), for effective population sizes between 10⁵ and 10⁸. The parameter values assumed were μ₁ = 6 × 10⁻⁵, μ₂ = 1.5 × 10⁻⁵, s₁ = 0.45, and s₂ = 0.28. Similar results were obtained with a wide range of parameter values.

FIG. 4

Change in viral load (VL) associated with the outgrowth of M184V for 16 individuals, together with the best fit obtained from maximum likelihood.

FIG. 5

Changes in the viral load (VL) before therapy (obtained by dividing initial viral load by viral load obtained 1 to 2 weeks prior to therapy) compared to the changes in viral load during therapy (obtained by dividing viral load 12 weeks into therapy by initial viral load) for individuals with low (<200) and high (≥200) CD4⁺ counts.