Analysis of HIV-1 pol sequences using Bayesian Networks: implications for drug resistance.
Human Immunodeficiency Virus-1 (HIV-1) antiviral resistance is a major cause of antiviral therapy failure and compromises future treatment options. As a consequence, resistance testing is the standard of care. Because of the high degree of HIV-1 natural variation and complex interactions, the role of resistance mutations is in many cases insufficiently understood. We applied a probabilistic model, Bayesian networks, to analyze direct influences between protein residues and exposure to treatment in clinical HIV-1 protease sequences from diverse subtypes. We can determine the specific role of many resistance mutations against the protease inhibitor nelfinavir, and determine relationships between resistance mutations and polymorphisms. We can show for example that in addition to the well-known major mutations 90M and 30N for nelfinavir resistance, 88S should not be treated as 88D but instead considered as a major mutation and explain the subtype-dependent prevalence of the 30N resistance pathway.
Deforche
K
K
Rega Institute for Medical Research, Katholieke Universiteit Leuven Leuven, Belgium. koen.deforche@uz.kuleuven.ac.be
Silander
T
T
Camacho
R
R
Grossman
Z
Z
Soares
M A
MA
Van Laethem
K
K
Kantor
R
R
Moreau
Y
Y
Vandamme
A-M
AM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001499:Bayes Theorem; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral / Q000502:physiology*; D015684:Gene Products, pol / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics*; D008957:Models, Genetic; D015233:Models, Statistical; D008969:Molecular Sequence Data; D009154:Mutation; D010363:Pattern Recognition, Automated / Q000379:methods; D016415:Sequence Alignment / Q000379:methods; D020539:Sequence Analysis, Protein / Q000379:methods*; D013329:Structure-Activity Relationship
D015684:Gene Products, pol