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.

[1]  Michael I. Jordan.  Learning in Graphical Models , 1999, NATO ASI Series.

[2]  A. Rachlis,et al.  Antiviral therapy. , 1989, Clinics in dermatology.

[3]  Luís Torgo,et al.  Knowledge Discovery in Databases: PKDD 2005, 9th European Conference on Principles and Practice of Knowledge Discovery in Databases, Porto, Portugal, October 3-7, 2005, Proceedings , 2005, PKDD.

[4]  Thomas Lengauer,et al.  Estimating HIV evolutionary pathways and the genetic barrier to drug resistance. , 2005, The Journal of infectious diseases.

[5]  David Heckerman,et al.  A Tutorial on Learning with Bayesian Networks , 1999, Innovations in Bayesian Networks.

[6]  R. Samudrala,et al.  Simple Linear Model Provides Highly Accurate Genotypic Predictions of HIV-1 Drug Resistance , 2003, Antiviral therapy.

[7]  Judea Pearl,et al.  Graphical Models for Probabilistic and Causal Reasoning , 1997, The Computer Science and Engineering Handbook.

[8]  Anne-Mieke Vandamme,et al.  Protease mutation M89I/V is linked to therapy failure in patients infected with the HIV-1 non-B subtypes C, F or G , 2005, AIDS.

[9]  Lynn Morris,et al.  Impact of HIV-1 Subtype and Antiretroviral Therapy on Protease and Reverse Transcriptase Genotype: Results of a Global Collaboration , 2005, PLoS medicine.

[10]  Rami Kantor,et al.  Drug resistance in non-subtype B HIV-1. , 2004, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[11]  Marcelo A. Soares,et al.  Impact of Nelfinavir Resistance Mutations on In Vitro Phenotype, Fitness, and Replication Capacity of Human Immunodeficiency Virus Type 1 with Subtype B and C Proteases , 2004, Antimicrobial Agents and Chemotherapy.

[12]  A. Vandamme,et al.  A Genotypic Drug Resistance Interpretation Algorithm that Significantly Predicts Therapy Response in HIV-1-Infected Patients , 2001, Antiviral therapy.

[13]  D. Brutlag,et al.  Discovering structural correlations in α‐helices , 1994 .

[14]  Matthew J. Gonzales,et al.  Human Immunodeficiency Virus Reverse Transcriptase and Protease Sequence Database: an expanded data model integrating natural language text and sequence analysis programs , 2001, Nucleic Acids Res..

[15]  Robert W. Shafer,et al.  Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance , 2002, Clinical Microbiology Reviews.

[16]  Dan Engelhard,et al.  Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir , 2004, Antimicrobial Agents and Chemotherapy.

[17]  Thomas Lengauer,et al.  Learning multiple evolutionary pathways from cross-sectional data , 2004, J. Comput. Biol..

[18]  Thomas Lengauer,et al.  Characterization of Novel HIV Drug Resistance Mutations Using Clustering, Multidimensional Scaling and SVM-Based Feature Ranking , 2005, PKDD.

[19]  Tulio de Oliveira,et al.  An automated genotyping system for analysis of HIV-1 and other microbial sequences , 2005, Bioinform..

[20]  Thomas D. Wu,et al.  Mutation Patterns and Structural Correlates in Human Immunodeficiency Virus Type 1 Protease following Different Protease Inhibitor Treatments , 2003, Journal of Virology.

[21]  Nir Friedman,et al.  Data Analysis with Bayesian Networks: A Bootstrap Approach , 1999, UAI.