HIV reverse transcriptase; molecular basis for drug resistance; gene therapy
Accepting graduate students
Director, McGill AIDS Centre
Lady Davis Institute
Jewish General Hospital
3755 Côte-Ste-Catherine Road
Montreal, QC H3T 1E2
Tel: (514) 340-8260 x.5282
Fax: (514) 340-7502
mark [dot] wainberg [at] mcgill [dot] ca (Email)
In the news
HIV strands can re-infect those already afflicted - CBC News
In conversation with Mark Wainberg - McGill Alumni Quarterly - winter 2000-01
Leading the charge against AIDS - McGill Reporter (Sep 10, 98)
Our lab focuses on the reverse transcriptase (RT) of HIV-1 in regard to each of basic mechanisms of action, inhibition by anti-viral drugs and drug resistance, and gene therapy.
We have been instrumental in demonstrating, together with colleagues, specific interactions among each of viral genomic RNA, reverse transcriptase, and tRNALys.3 primer molecules that act jointly to promote RT activity. We have constructed a series of mutations within viral genomic RNA that adversely affect viral RT activity. In some cases, substitution of alternate sequences within the primer binding site (PBS) of HIV RNA can lead to utilization of alternate tRNA molecules as primers of RT.
Our lab has also studied a variety of drugs that antagonize both HIV RT activity and viral replication. Two series of compounds have been extensively analyzed in our laboratory — nucleoside inhibitors of RT, such as AZT and 3TC, as well as a series of non-nucleoside RT inhibitors (NNRTI). 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 both types of compounds in tissue culture and in the clinic. In each instance, mutations in the RT gene can be shown by site-directed mutagenesis to possess biological relevance. Recombinant 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.
We have also designed a series of mutated viral constructs that contain deletions in the non-coding region of the HIV genome. The object is to functionally characterize this region and to determine whether these deleted viruses may be able to serve as candidates for an attenuated HIV vaccine.
Selected Recent Publications
Diallo K, Gotte M, Wainberg MA. Molecular Impact of the M184V Mutation in Human Immunodeficiency Virus Type 1 Reverse Transcriptase. Antimicrob Agents Chemother. 2003 Nov;47(11):3377-83. No abstract available.
Turner D, Brenner B, Wainberg MA. Multiple Effects of the M184V Resistance Mutation in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1. Clin Diagn Lab Immunol. 2003 Nov;10(6):979-81. No abstract available.
Quan Y, Brenner BG, Marlink RG, Essex M, Kurimura T, Wainberg MA. Drug resistance profiles of recombinant reverse transcriptases from human immunodeficiency virus type 1 subtypes A/E, B, and C. AIDS Res Hum Retroviruses. 2003 Sep;19(9):743-53.
Wainberg MA. HIV resistance to nevirapine and other non-nucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr. 2003 Sep;34 Suppl 1:S2-7. Review.
Germinario RJ, Colby-Germinario SP, Cammalleri C, Wainberg MA. The long-term effects of anti-retroviral protease inhibitors on sugar transport in L6 cells. J Endocrinol. 2003 Sep;178(3):449-56.
Diallo K, Marchand B, Wei X, Cellai L, Gotte M, Wainberg MA. Diminished RNA primer usage associated with the L74V and M184V mutations in the reverse transcriptase of human immunodeficiency virus type 1 provides a possible mechanism for diminished viral replication capacity. J Virol. 2003 Aug;77(16):8621-32.
Diallo K, Brenner B, Oliveira M, Moisi D, Detorio M, Gotte M, Wainberg MA. The M184V substitution in human immunodeficiency virus type 1 reverse transcriptase delays the development of resistance to amprenavir and efavirenz in subtype B and C clinical isolates. Antimicrob Agents Chemother. 2003 Jul;47(7):2376-9.
Youle M, Wainberg MA. Pre-exposure chemoprophylaxis (PREP) as an HIV prevention strategy. J Int Assoc Physicians AIDS Care (Chic Ill). 2003 Jul-Sep;2(3):102-5.
Wei X, Liang C, Gotte M, Wainberg MA. Negative effect of the M184V mutation in HIV-1 reverse transcriptase on initiation of viral DNA synthesis. Virology. 2003 Jun 20;311(1):202-12.
Klein MB, Campeol N, Lalonde RG, Brenner B, Wainberg MA. Didanosine, interferon-alfa and ribavirin: a highly synergistic combination with potential activity against HIV-1 and hepatitis C virus. AIDS. 2003 May 2;17(7):1001-8.
Youle M, Wainberg MA. Could chemoprophylaxis be used as an HIV prevention strategy while we wait for an effective vaccine? AIDS. 2003 Apr 11;17(6):937-8. No abstract available.
Guo X, Kameoka M, Wei X, Roques B, Gotte M, Liang C, Wainberg MA. Suppression of an intrinsic strand transfer activity of HIV-1 Tat protein by its second-exon sequences. Virology. 2003 Mar 1;307(1):154-63.
Quan Y, Brenner BG, Oliveira M, Wainberg MA. Lamivudine can exert a modest antiviral effect against human immunodeficiency virus type 1 containing the M184V mutation. Antimicrob Agents Chemother. 2003 Feb;47(2):747-54.
Liang C, Hu J, Whitney JB, Kleiman L, Wainberg MA. A structurally disordered region at the C terminus of capsid plays essential roles in multimerization and membrane binding of the gag protein of human immunodeficiency virus type 1. J Virol. 2003 Feb;77(3):1772-83.
Brenner B, Turner D, Oliveira M, Moisi D, Detorio M, Carobene M, Marlink RG, Schapiro J, Roger M, Wainberg MA. A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors. AIDS. 2003 Jan 3;17(1):F1-5.