Expanded Spectrum of Antiretroviral-Selected Mutations in Human Immunodeficiency Virus Type 2.

INTRODUCTION HIV-1 and HIV-2 differ in their antiretroviral (ARV) susceptibilities and drug resistance mutations (DRMs). METHODS We analyzed published HIV-2 pol sequences to identify HIV-2 treatment-selected mutations (TSMs). Mutation prevalences were determined by HIV-2 group and ARV status. Nonpolymorphic mutations were those in <1% of ARV-naïve persons. TSMs were those associated with ARV therapy after multiple comparisons adjustment. RESULTS We analyzed protease (PR) sequences from 483 PR inhibitor (PI)-naïve and 232 PI-treated persons; RT sequences from 333 nucleoside RT inhibitor (NRTI)-naïve and 252 NRTI-treated persons; and integrase (IN) sequences from 236 IN inhibitor (INSTI)-naïve and 60 INSTI-treated persons. In PR, 12 nonpolymorphic TSMs occurred in ≥11 persons: V33I, K45R, V47A, I50V, I54M, T56V, V62A, A73G, I82F, I84V, F85L, L90M. In RT, 9 nonpolymorphic TSMs occurred in ≥10 persons: K40R, A62V, K70R, Y115F, Q151M, M184VI, S215Y. In IN, 11 nonpolymorphic TSMs occurred in ≥4 persons: Q91R, E92AQ, T97A, G140S, Y143G, Q148R, A153G, N155H, H156R, R231 5-amino acid insertions. Nine of 32 nonpolymorphic TSMs were previously unreported. CONCLUSIONS This meta-analysis confirmed the ARV association of previously reported HIV-2 DRMs and identified novel TSMs. Genotypic and phenotypic studies of HIV-2 TSMs will improve approaches to predicting HIV-2 ARV susceptibility and treating HIV-2-infected persons.

[1]  C. Charpentier,et al.  A new mechanism of resistance of HIV-2 to integrase inhibitors: a 5 amino-acids insertion in the integrase C-terminal domain. , 2018, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[2]  F. Månsson,et al.  Long-term follow-up of HIV-2-related AIDS and mortality in Guinea-Bissau: a prospective open cohort study. , 2018, The lancet. HIV.

[3]  F. Brun-Vézinet,et al.  Cellular and plasma viral load in patients infected with HIV‐2 , 1993, AIDS.

[4]  F. Brun-Vézinet,et al.  High frequency of selection of K65R and Q151M mutations in HIV‐2 infected patients receiving nucleoside reverse transcriptase inhibitors containing regimen , 2004, Journal of medical virology.

[5]  J. Mendieta,et al.  Amino acid residues in HIV-2 reverse transcriptase that restrict the development of nucleoside analogue resistance through the excision pathway , 2017, The Journal of Biological Chemistry.

[6]  V. Soriano,et al.  Drug resistance mutations in HIV-2 patients failing raltegravir and influence on dolutegravir response , 2017, The Journal of antimicrobial chemotherapy.

[7]  Mar Alvarez,et al.  Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection. , 2014, Antiviral research.

[8]  C. Charpentier,et al.  G140S/Q148R and N155H mutations render HIV-2 Integrase resistant to Raltegravir whereas Y143C does not , 2011, Retrovirology.

[9]  J. Mullins,et al.  Three Main Mutational Pathways in HIV-2 Lead to High-Level Raltegravir and Elvitegravir Resistance: Implications for Emerging HIV-2 Treatment Regimens , 2012, PloS one.

[10]  K. White,et al.  HIV-2 Antiviral Potency and Selection of Drug Resistance Mutations by the Integrase Strand Transfer Inhibitor Elvitegravir and NRTIs Emtricitabine and Tenofovir In Vitro , 2013, Journal of acquired immune deficiency syndromes.

[11]  Presence of a multidrug-resistance mutation in an HIV-2 variant infecting a treatment-naive individual in Caio, Guinea Bissau. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[12]  Arun K. Ghosh,et al.  Critical differences in HIV‐1 and HIV‐2 protease specificity for clinical inhibitors , 2012, Protein science : a publication of the Protein Society.

[13]  M. Aickin,et al.  Adjusting for multiple testing when reporting research results: the Bonferroni vs Holm methods. , 1996, American journal of public health.

[14]  G. Marcaida,et al.  Clinical experience with integrase inhibitors in HIV-2-infected individuals in Spain , 2019, The Journal of antimicrobial chemotherapy.

[15]  G. Gottlieb,et al.  Emergence of multiclass drug-resistance in HIV-2 in antiretroviral-treated individuals in Senegal: implications for HIV-2 treatment in resouce-limited West Africa. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[16]  B. Rodés,et al.  High rate of proV47A selection in HIV-2 patients failing lopinavir-based HAART , 2006, AIDS.

[17]  A. Vandamme,et al.  Mutations selected in HIV-2-infected patients failing a regimen including atazanavir. , 2013, The Journal of antimicrobial chemotherapy.

[18]  D. Ho,et al.  Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251 , 2017, AIDS.

[19]  C. Charpentier,et al.  Genotypic resistance profiles of HIV-2-treated patients in West Africa , 2014, AIDS.

[20]  G. Gottlieb,et al.  In vitro activity of dolutegravir against wild-type and integrase inhibitor-resistant HIV-2 , 2015, Retrovirology.

[21]  F. Brun-Vézinet,et al.  In Vitro Phenotypic Susceptibility of Human Immunodeficiency Virus Type 2 Clinical Isolates to Protease Inhibitors , 2008, Antimicrobial Agents and Chemotherapy.

[22]  C. Charpentier,et al.  In-vitro phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitor S/GSK1349572 , 2010, AIDS.

[23]  G. Gottlieb,et al.  90-90-90 for HIV-2? Ending the HIV-2 epidemic by enhancing care and clinical management of patients infected with HIV-2. , 2018, The lancet. HIV.

[24]  P. Coveney,et al.  Mutation V111I in HIV-2 Reverse Transcriptase Increases the Fitness of the Nucleoside Analogue-Resistant K65R and Q151M Viruses , 2014, Journal of Virology.

[25]  G. Gottlieb,et al.  Complex Patterns of Protease Inhibitor Resistance among Antiretroviral Treatment-Experienced HIV-2 Patients from Senegal: Implications for Second-Line Therapy , 2013, Antimicrobial Agents and Chemotherapy.

[26]  R. Gangakhedkar,et al.  Partial pol Sequences from Drug Naive HIV-2 Infected Individuals from Maharashtra, India. , 2019, AIDS research and human retroviruses.

[27]  S. Rowland-Jones,et al.  Virological and immunological response to Combivir and emergence of drug resistance mutations in a cohort of HIV-2 patients in The Gambia , 2006, AIDS.

[28]  V. Soriano,et al.  Drug resistance mutations in patients infected with HIV-2 living in Spain. , 2011, The Journal of antimicrobial chemotherapy.

[29]  F. Brun-Vézinet,et al.  Polymorphism of the Human Immunodeficiency Virus Type 2 (HIV-2) Protease Gene and Selection of Drug Resistance Mutations in HIV-2-Infected Patients Treated with Protease Inhibitors , 2005, Journal of Clinical Microbiology.

[30]  S. Sarafianos,et al.  Why Do HIV-1 and HIV-2 Use Different Pathways to Develop AZT Resistance? , 2006, PLoS pathogens.

[31]  M. Wainberg,et al.  Antiretroviral Drug Resistance in Human Immunodeficiency Virus Type 2 , 2009, Antimicrobial Agents and Chemotherapy.

[32]  D. Stuart,et al.  Structure of HIV-2 reverse transcriptase at 2.35-Å resolution and the mechanism of resistance to non-nucleoside inhibitors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Glenn Lawyer,et al.  COMET: adaptive context-based modeling for ultrafast HIV-1 subtype identification , 2014, Nucleic acids research.

[34]  F. Gao,et al.  In Vitro Selection and Characterization of Human Immunodeficiency Virus Type 2 with Decreased Susceptibility to Lopinavir , 2007, Antimicrobial Agents and Chemotherapy.

[35]  C. Charpentier,et al.  Dolutegravir in HIV-2-Infected Patients With Resistant Virus to First-line Integrase Inhibitors From the French Named Patient Program. , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[36]  G. Gottlieb,et al.  Four Amino Acid Changes in HIV-2 Protease Confer Class-Wide Sensitivity to Protease Inhibitors , 2015, Journal of Virology.

[37]  I. Thior,et al.  Reduced rate of disease development after HIV-2 infection as compared to HIV-1. , 1994, Science.

[38]  Arun K. Ghosh,et al.  Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I. , 2019, Biochemical and biophysical research communications.

[39]  P. Colson,et al.  Polymorphism and Drug-Selected Mutations in the Protease Gene of Human Immunodeficiency Virus Type 2 from Patients Living in Southern France , 2004, Journal of Clinical Microbiology.

[40]  Obi L. Griffith,et al.  HIV Sequence Database , 2014 .

[41]  R. Camacho.  Special Aspects of the Treatment of HIV-2-Infected Patients , 2012, Intervirology.

[42]  P. Boyer,et al.  HIV-1 and HIV-2 Reverse Transcriptases: Different Mechanisms of Resistance to Nucleoside Reverse Transcriptase Inhibitors , 2012, Journal of Virology.

[43]  P. Coveney,et al.  Mutation V111I in HIV-2 Reverse Transcriptase Increases the Fitness of the Nucleoside Analogue-Resistant K65R and Q151M Viruses , 2014, Journal of Virology.

[44]  B. Rodés,et al.  Susceptibility to protease inhibitors in HIV-2 primary isolates from patients failing antiretroviral therapy. , 2006, The Journal of antimicrobial chemotherapy.

[45]  G. Gottlieb,et al.  Antiretroviral drug resistance in HIV-2: three amino acid changes are sufficient for classwide nucleoside analogue resistance. , 2009, The Journal of infectious diseases.

[46]  P. Colson,et al.  Polymorphism and drug‐selected mutations in the reverse transcriptase gene of HIV‐2 from patients living in southeastern France , 2005, Journal of medical virology.

[47]  G. Gottlieb,et al.  Phenotypic susceptibility of HIV-2 to raltegravir: integrase mutations Q148R and N155H confer raltegravir resistance , 2011, AIDS.

[48]  K. Van Laethem,et al.  Transmitted drug resistance, selection of resistance mutations and moderate antiretroviral efficacy in HIV-2: Analysis of the HIV-2 Belgium and Luxembourg database , 2008, BMC infectious diseases.

[49]  F. Brun-Vézinet,et al.  In vitro Phenotypic Susceptibility to Nucleoside Reverse Transcriptase Inhibitors of HIV-2 Isolates with the Q151M Mutation in the Reverse Transcriptase Gene , 2005, Antiviral therapy.