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Stochastic processes strongly influence HIV-1 evolution during suboptimal protease-inhibitor therapy
M Nijhuis1, C A Boucher, P Schipper
1Eijkman-Winkler Institute, Department of Virology, University Hospital Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Summary
Human immunodeficiency virus type 1 (HIV-1) evolution is influenced by chance, not just deterministic models. Stochastic models better describe HIV-1 evolution due to small effective population size and genetic bottlenecks during treatment.
Area of Science:
- Virology
- Evolutionary Biology
- Genetics
Background:
- HIV-1 evolution was traditionally viewed as deterministic due to large population sizes.
- Recent suggestions propose a smaller effective population size (Ne), allowing stochastic (chance) factors to influence evolution.
Purpose of the Study:
- To experimentally investigate whether ritonavir resistance development impacts HIV-1 env gene evolution.
- To gather evidence to support either deterministic or stochastic evolutionary models for HIV-1.
Main Methods:
- Analysis of sequential serum samples from five patients treated with ritonavir.
- Sequencing of protease and env gene V3 domains.
- Phylogenetic tree construction, genetic variation calculation, and Ne estimation.
Main Results:
- All patients developed genotypic resistance to ritonavir with unique mutation combinations, suggesting stochasticity.
- HIV-1 env gene experienced significant population bottlenecking during treatment (P < 0.025).
- Estimated Ne was small (500-15,000) compared to total viral RNA copy number.
Conclusions:
- The study provides evidence supporting stochastic evolutionary models for HIV-1.
- Key indicators include population bottlenecking, small effective population size, and varied resistance mutation pathways.