Bayesian network analyses of resistance pathways against efavirenz and nevirapine

Objective:To clarify the role of novel mutations selected by treatment with efavirenz or nevirapine, and investigate the influence of HIV-1 subtype on nonnucleoside reverse transcriptase inhibitor (nNRTI) resistance pathways. Design:By finding direct dependencies between treatment-selected mutations, the involvement of these mutations as minor or major resistance mutations against efavirenz, nevirapine, or coadministrated nucleoside analogue reverse transcriptase inhibitors (NRTIs) is hypothesized. In addition, direct dependencies were investigated between treatment-selected mutations and polymorphisms, some of which are linked with subtype, and between NRTI and nNRTI resistance pathways. Methods:Sequences from a large collaborative database of various subtypes were jointly analyzed to detect mutations selected by treatment. Using Bayesian network learning, direct dependencies were investigated between treatment-selected mutations, NRTI and nNRTI treatment history, and known NRTI resistance mutations. Results:Several novel minor resistance mutations were found: 28K and 196R (for resistance against efavirenz), 101H and 138Q (nevirapine), and 31L (lamivudine). Robust interactions between NRTI mutations (65R, 74V, 75I/M, and 184V) and nNRTI resistance mutations (100I, 181C, 190E and 230L) may affect resistance development to particular treatment combinations. For example, an interaction between 65R and 181C predicts that the nevirapine and tenofovir and lamivudine/emtricitabine combination should be more prone to failure than efavirenz and tenofovir and lamivudine/emtricitabine. Conclusion:Bayesian networks were helpful in untangling the selection of mutations by NRTI versus nNRTI treatment, and in discovering interactions between resistance mutations within and between these two classes of inhibitors.

[1]  J. Corbeil,et al.  Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy , 1994, Journal of virology.

[2]  M. Wainberg,et al.  Higher fidelity of RNA-dependent DNA mispair extension by M184V drug-resistant than wild-type reverse transcriptase of human immunodeficiency virus type 1. , 1997, Nucleic acids research.

[3]  P. Boyer,et al.  A Mutation at Position 190 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Interacts with Mutations at Positions 74 and 75 via the Template Primer , 1998, Antimicrobial Agents and Chemotherapy.

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

[5]  Martine Peeters,et al.  Genetic Diversity of Protease and Reverse Transcriptase Sequences in Non-Subtype-B Human Immunodeficiency Virus Type 1 Strains: Evidence of Many Minor Drug Resistance Mutations in Treatment-Naive Patients , 2000, Journal of Clinical Microbiology.

[6]  D I Stuart,et al.  Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. , 2000, Structure.

[7]  Zehava Grossman,et al.  Genotypic variation of HIV-1 reverse transcriptase and protease: comparative analysis of clade C and clade B , 2001, AIDS.

[8]  D. Katzenstein,et al.  Phenotypic hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in treatment-experienced HIV-infected patients: impact on virological response to efavirenz-based therapy , 2001, AIDS.

[9]  K. Ariyoshi,et al.  Impact of baseline polymorphisms in RT and protease on outcome of highly active antiretroviral therapy in HIV-1-infected African patients , 2001, AIDS.

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

[11]  K. Hertogs,et al.  Testing Genotypic and Phenotypic Resistance in Human Immunodeficiency Virus Type 1 Isolates of Clade B and Other Clades from Children Failing Antiretroviral Therapy , 2002, Journal of Clinical Microbiology.

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

[13]  M. Wainberg,et al.  Multiple Effects of the M184V Resistance Mutation in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 , 2003, Clinical Diagnostic Laboratory Immunology.

[14]  Kaneo Yamada,et al.  Patterns of point mutations associated with antiretroviral drug treatment failure in CRF01_AE (subtype E) infection differ from subtype B infection. , 2003, Journal of acquired immune deficiency syndromes.

[15]  M. Wainberg,et al.  A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors , 2003, AIDS.

[16]  B. Canard,et al.  The Y181C Substitution in 3′-Azido-3′-deoxythymidine-resistant Human Immunodeficiency Virus, Type 1, Reverse Transcriptase Suppresses the ATP-mediated Repair of the 3′-Azido-3′-deoxythymidine 5′-Monophosphate-terminated Primer* , 2003, Journal of Biological Chemistry.

[17]  J. Schapiro,et al.  Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C , 2004, AIDS.

[18]  Ronald J Bosch,et al.  Genetic correlates of efavirenz hypersusceptibility , 2004, AIDS.

[19]  J. Schapiro,et al.  Antiretroviral Drug Resistance in Non-Subtype B HIV-1, HIV-2 and Siv , 2004, Antiviral therapy.

[20]  Tommy F. Liu,et al.  HIV-1 Protease and reverse-transcriptase mutations: correlations with antiretroviral therapy in subtype B isolates and implications for drug-resistance surveillance. , 2005, The Journal of infectious diseases.

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

[22]  Yves Moreau,et al.  Analysis of HIV-1 pol sequences using Bayesian Networks: implications for drug resistance , 2006, Bioinform..

[23]  Klaus Korn,et al.  The Calculated Genetic Barrier for Antiretroviral Drug Resistance Substitutions Is Largely Similar for Different HIV-1 Subtypes , 2006, Journal of acquired immune deficiency syndromes.

[24]  S. Lo Caputo,et al.  Impact of unreported HIV‐1 reverse transcriptase mutations on phenotypic resistance to nucleoside and non‐nucleoside inhibitors , 2006, Journal of medical virology.

[25]  Christos J. Petropoulos,et al.  The K101P and K103R/V179D Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Resistance to Nonnucleoside Reverse Transcriptase Inhibitors , 2006, Antimicrobial Agents and Chemotherapy.

[26]  Thomas Lengauer,et al.  Involvement of Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutations in the Regulation of Resistance to Nucleoside Inhibitors , 2006, Journal of Virology.

[27]  Hannah Green,et al.  Identification of accessory mutations associated with high-level resistance in HIV-1 reverse transcriptase , 2007, AIDS.

[28]  Thomas Lengauer,et al.  Characterization and Structural Analysis of Novel Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Involved in the Regulation of Resistance to Nonnucleoside Inhibitors , 2007, Journal of Virology.

[29]  Anne-Mieke Vandamme,et al.  Antiretroviral resistance in different HIV-1 subtypes: impact on therapy outcomes and resistance testing interpretation , 2007, Current opinion in HIV and AIDS.

[30]  D. Richman,et al.  Update of the drug resistance mutations in HIV-1: 2007. , 2007, Topics in HIV medicine : a publication of the International AIDS Society, USA.

[31]  Susan Olender,et al.  Advances in antiretroviral therapy. , 2009, Topics in HIV medicine : a publication of the International AIDS Society, USA.

[32]  D. Richman,et al.  2022 update of the drug resistance mutations in HIV-1. , 2022, Topics in antiviral medicine.