title: Estimating HIV evolutionary pathways and the genetic barrier to drug resistance.
abstract: BACKGROUND
  The evolution of drug-resistant viruses challenges the management of human immunodeficiency virus (HIV) infections. Understanding this evolutionary process is important for the design of effective therapeutic strategies.
  
  
  METHODS
  We used mutagenetic trees, a family of probabilistic graphical models, to describe the accumulation of resistance-associated mutations in the viral genome. On the basis of these models, we defined the genetic barrier, a quantity that summarizes the difficulty for the virus to escape from the selective pressure of the drug by developing escape mutations.
  
  
  RESULTS
  From HIV reverse-transcriptase sequences that had been obtained from treated patients, we derived evolutionary models for zidovudine, zidovudine plus lamivudine, and zidovudine plus didanosine. The genetic barriers to resistance to zidovudine, stavudine, lamivudine, and didanosine, for the above 3 regimens, were computed and analyzed. We found both the mode and the rate of development of resistance to be heterogeneous. The genetic barrier to zidovudine resistance was increased if lamivudine was added to zidovudine but was decreased for didanosine. The barrier to lamivudine resistance was maintained with zidovudine plus didanosine, whereas the barrier to didanosine resistance was reduced most with zidovudine plus lamivudine.
  
  
  CONCLUSIONS
  Mutagenetic trees provide a quantitative picture of the evolution of drug resistance. The genetic barrier is a useful tool for design of effective treatment strategies.
authors.affiliation: Max Planck Institute for Informatics, Saarbrucken, Germany. niko@math.berkeley.edu
authors.forename: Niko
authors.initials: N
authors.lastname: Beerenwinkel
authors.forename: Martin
authors.initials: M
authors.lastname: Däumer
authors.forename: Tobias
authors.initials: T
authors.lastname: Sing
authors.forename: Jörg
authors.initials: J
authors.lastname: Rahnenfuhrer
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.forename: Joachim
authors.initials: J
authors.lastname: Selbig
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoffmann
authors.forename: Rolf
authors.initials: R
authors.lastname: Kaiser
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D005075:Biological Evolution; D024882:Drug Resistance, Viral / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation
chemical_list: D019380:Anti-HIV Agents