In Memoriam: Dr. Mark Wainberg

Dr. Mark WainbergDr. Mark Wainberg, 1945 - 2017

Professor
Molecular Biology/ Virology

Senior Investigator, Lady Davis Institute
Director of the McGill University AIDS Centre

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Research Interests

 

HIV reverse transcriptase; molecular basis for drug resistance; gene therapy

Research Orientation

Our lab focuses on the integrase (IN) and reverse transcriptase (RT) enzymes of HIV-1 in regard to each of basic mechanisms of action, inhibition by anti-viral drugs, and drug resistance.

Our lab has also studied a variety of drugs that antagonize both HIV integrase and RT activity and viral replication. Three series of compounds have been extensively analyzed in our laboratory, i.e. nucleoside inhibitors of RT, such as AZT and 3TC; a series of non-nucleoside RT inhibitors (NNRTI); and integrase strand transfer inhibitors (INSTIs). The former act as chain terminators of nascent DNA while the NNRTIs function as non-competitive inhibitors of enzyme activity. Resistance can be selected against each types of compound in tissue culture and in the clinic.  Mutations in the IN and RT genes can be shown by site-directed mutagenesis to possess biological relevance. Recombinant IN and RT molecules that contain relevant amino acid substitutions have been shown to be resistant to these drugs in enzyme assays. Our lab is currently studying how to prevent drug resistance-conferring mutations from arising.

Appointments

  • Director of the McGill University AIDS Centre
  • Head of the HIV/AIDS research axis, Lady Davis Institute

Book Chapters

  • Sluis-Cremer N, Wainberg MA and Schinazi RF. Resistance to reverse transcriptase inhibitors used in the treatment and prevention of HIV-1 infection.  Future Microbiology 2015. 10(11), 1773-1782
  • Wainberg MA.  Early HIV treatment to forestall drug resistance. The Lancet Infectious Diseases Published online January 28, 2016 http://dx.doi.org/10.1016/S1473-3099(16)00013-X
  • Wainberg MA, Han YS, and Mesplede T.  Might Dolutegravir be part of a functional cure for HIV? Canadian Journal of Microbiology 2016. 62:1-8
  • Mesplede T, Wainberg MA.  Will LEDGIN Molecules Be Able to Play a Role in a Cure for HIV Infection? EBiomedicine 2016. 8: 14-15.
  • Hassounah SA, Mesplede T, Wainberg MA. Nonhuman Primates and Humanized Mice for Studies of HIV-1 Integrase Inhibitors: A Review. Pathogens and Immunity 2016. 1(1)41-67.
  • Liang C, Wainberg MA, Das AT, and  Berkhout B. CRISPR/Cas9: a double-edged sword when used to combat HIV infection. Retrovirology 2016; 13: 37.
  • Han YS, Mesplede T, Wainberg MA. Differences among HIV-1 subtypes in drug resistance against integrase inhibitors.  Infection, Genetics and Evolution. 2016.  doi:10.1016/j.meegid.2016.06.047

Selected Publications

  • Brenner B, Thomas R Blanco J, Ibanescu R-I, Oliveira M, Mesplede T,  Golubkov O,  Roger M, Garcia F, Martinez E. Wainberg MA. Development of a G118R Mutation in HIV-1 Integrase following a  Switch to Dolutegravir Monotherapy  Leading  to Cross-Resistance to Integrase Inhibitors. Journal of Antimicrobial Chemotherapy 2016. Doi:10.1093/jac/dkw071
  • Anstett K, Cutillas V, Fusco R, Mesplede T, and Wainberg MA. The polymorphic substitution E157Q in HIV-1 integrase increases R263K-mediated dolutegravir resistance and decreases DNA binding activity. Journal of Antimicrobial Chemotherapy 2016. doi:10.1093/jac/dkw109
  • Wang Z, Pan Q, Gendron P, Zhu W, Guo F, Cen S, Wainberg MA, Liang C. CRISPR/Cas9-derived mutations both inhibit HIV-1 replication and accelarated viral escape. Cell Reports 15, 1-9, 2016. Http://dx.doi.org/10.1016/j.celrep.2016.03.042
  • Pham HT, Mesplede T, Wainberg MA. Effect on HIV-1 viral replication capacity of DTG-resistance mutations in NRTI/NNRTI resistant viruses. Retrovirology 2016. 13:31. Doi 10.1186/s12977-016-0265-x
  • Liang C, Wainberg MA, Das AT and Berkhout B. CRISPR/Cas9: a double-edged sword when used to combat HIV infection.  Retrovirology 2016. 13:37. DOI 10.1186/s12977-016-0270-0.
  • Oliveira M, Ibanescu RI, Thi Pham H, Brenner B, Mesplède T, and Wainberg MA. The M184I/V and K65R nucleoside resistance mutations in HIV-1 prevent the emergence of resistance mutations against dolutegravir. AIDS 2016. DOI: 10.1097/QAD.0000000000001191
  • Depatureaux A, Quashie PK, Mesplede T, Han Y, Koubi H, Plantier JF, Oliveira M, Moisi D, Brenner B, Wainberg MA.  HIV-1 Group O Integrase Displays Lower Enzymatic Efficiency and Higher Susceptibility to Raltegravir than HIV-1 Group M Subtype B Integrase.  Antimicrobial Agents and Chemotherapy. 2014, 58(12): 7141-7151.
  • JM Yue, Zao JX, Liu CP, Qi WY, Han ML, Wainberg MA, Han Y. Eurifoloids A-R, Structurally Diverse Diterpenoids from Euphorbia neriifolia. Journal of Natural Products 2014;77(10):2224-33.
  • Quan Y, Xu H, Kramer VG, Han Y, Sloan R, and Wainberg MA. Identification of an Env-defective HIV-1 mutant capable of spontaneous reversion to a wild-type phenotype in certain T-cell lines. Virology Journal. 2014; 11:177
  • Liu, C-P; Xu, J-B; Wainberg, MA; Han, Y-S, Yue, J-M;. Trichiconins A-C, Limonoids with New Carbon Skeletons from Trichilia Connaroides. Organic Letters 2014;16(20):5478-81.
  • Xu JB, Zhang H, Gan LS, Han Y, Wainberg MA, and Yue JM. Logeracemin A, an anti-HIV daphniphyllum alkaloid dimer with a new carbon skeleton from daphniphyllum longeracemosum. Journal of the American  Chemical Society 2014. 136,7631-7633.
  • Liu CP, Xu JB, Han Y, Wainberg MA, and Yue JM. Trichiconins A-C, limonoids with new carbon skeletons from trichilia connaroides. Organic Letters 2014. 16,5478-5481.
  • Zhao JX, Liu CP, Qi WY, Han ML, Han Y, Wainberg MA, and Yue JM. A−R, Eurifoloids structurally diverse diterpenoids from euphorbia neriifolia. Journal of Natural Products. 2014. 77, 2224-2233.
  • Hardy I, Brenner B, Quashie P, Thomas R, Petropoulos c, Huang W, Moisi D, Wainberg MA, Roger M. Evolution of a novel pathway leading to dolutegravir resistance in a patient harboring N155H and multiclass drug resistance J. Antimicrobial Chemotherapy 2015;70(2):405-11.
  • Kramer V, Hassounah S, Colby-Germinario S, Oliveira M, Lefebvre E, Mesplede T, Wainberg MA. The dual CCR5 and CCR2 inhibitor Cenicriviroc does not redistribute HIV into extracellular space: implicaitons for plasma viral load and intracellular DNA decline. Journal of Antimicrobial Chemotherapy. 2015; 70(3):750-756.
  • Cutillas V, Mesplede T, Anstett K, Hassounah S, Wainberg MA. The addition of R262K to the H51Y mutation in HIV-1 subtype B integrase confers low-level resistance against dolutegravir.Antimicrobial Agents & Chemotherapy 2015. 59(1):310-6
  • Quashie PK, Oliviera M, Veres T, Osman N, Han YS, Hassounah S, Lie Y, Huang W, Mesplède T, and Wainberg MA. Differential effects of the G118R, H51Y and E138K resistance substitutions in different subtypes of HIV integrase. J. Virol 2015. 89(6):3163-75
  • Anstett K, Mesplede T, Oliveira M, Cutillas V, and Wainberg MA. The Dolutegravir-Resistance Mutation R263K Cannot Co-Exist in Combination with Many Classical Integrase Inhibitor Resistance Substitutions. J. Virol 2015. 89(8)4681-4684
  • Wares M., Hassounah S, Mesplède T, Sandstrom PA, Wainberg MA. Simian-tropic HIV as a model to study drug resistance against integrase inhibitors. Antimicrob Agents Chemother. 2015;59(4):1942-9.
  • Zhu W, Lei R, Le Duff Y, Li J, Guo F, Wainberg MA, and Liang C. The CRISPR/Cas9 system inactivates latent HIV-1 proviral DNA. Retrovirology 2015;12(1):22.
  • Depatureaux A, LeBlanc R, Moisi D, Brenner B, and Wainberg MA. The first report of HIV-1 group O infection in Canada. J Infect Dis Ther 2015. 3:1
  • Xu HT, Colby-Germinario SP, Quashie PK, Bethell R, and Wainberg MA. Subtype-specific analysis of the K65R substitution in HIV-1 that confers hypersusceptibility to a novel nucleotide-competing reverse transcriptase inhibitor. Antimicrobial Agents & Chemotherapy 2015. 59(6):3189-96
  • Campos N, Myburgh R, Garcel A, Vautrin A, Lapasset L, Nadal ES, Mahuteau F, Naijman R, Fornarelli P, Tantale K, Basyuk E, Séveno M, Venables JP, Pau B, Bertrand E, Wainberg MA, Speck R, Scherrer D and Tazi J. Long lasting control of viral rebound with a new drug ABX464 targeting Rev - mediated viral RNA biogenesis. Retrovirology 2015. 12:30
  • Han Y-S, Xiao W-L, Xu HT, Kramer VG, Quan Y , Mesplède T, Oliveira M, Colby-Germinario SP, Sun HD, and Wainberg MA,Identification of a dibenzocyclooctadiene lignan as a HIV-1 non nucleoside reverse transcriptase inhibitor. Antiviral Chemistry & Chemotherapy 2015. 24(1)28-39.
  • Mesplede T, Moisi D, Oliveira M, Ibanescu I, Ohnona F, Brenner B, Wainberg MA.  Dolutegravir inhibits HIV-1 Env evolution in primary human cells. AIDS 2015. 29(6):659-65
  • Singhroy DN, Wainberg MA, and Mesplede T. The combination of the R263K and M184I/V resistance mutations against dolutegravir and lamivudine decreases HIV viral fitness. Antimicrob. Agents Chemother 2015. 59(5)2882-2885
  • Zhang H, Han Y, Wainberg MA, Yue JM. Anti-HIV Securinega alkaloid oligomers from Flueggea virosa. Tetrahedron 2015. 71, 3671-3679
  • Quashie PK, Han YS, Hassounah S, Mesplede T, and Wainberg MA. Structural studies of the HIV-1 integrase protein: Compound screening and characterization of a DNA-binding inhibitor. PLOS ONE 2015 10(6):e0128310