Estimating HIV evolutionary pathways and the genetic barrier to drug resistance.
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.
Beerenwinkel
Niko
N
Max Planck Institute for Informatics, Saarbrucken, Germany. niko@math.berkeley.edu
Däumer
Martin
M
Sing
Tobias
T
Rahnenfuhrer
Jörg
J
Lengauer
Thomas
T
Selbig
Joachim
J
Hoffmann
Daniel
D
Kaiser
Rolf
R
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
D019380:Anti-HIV Agents