Associate Professor;
Molecular Biology/Virology
Virus-cell interactions in the regulation of HIV expression and replication
Virus-cell interactions laboratory
Lady Davis Institute for Medical Research, Room 523
3999 Côte-Ste-Catherine Road
Montreal, QC H3T 1E2
Tel: (514) 340-8222 x.5284
Fax: (514) 340-7576
anne [dot] gatignol [at] mcgill [dot] ca (Email)
Current lab members (12/2008):
Aïcha Daher, Research Associate
Guerline Clerzius, PhD candidate, Experimental Medicine
Sylvanne Daniels, PhD candidate, Microbiology & Immunology
Robert Scarborough, M.Sc. candidate, Microbiology & Immunology
Jean-François Gélinas, M.Sc. candidate, Microbiology & Immunology
Research Orientations
Virus-cell interactions control many steps in viral expression and replication. Viral proteins and RNAs use cellular components for their function and act on cellular mechanisms. In response, cellular pathways interfere with viruses, which results in helping or counteracting viral replication. We study the regulation of these mechanisms in the context of the Human Immunodeficiency Virus (HIV) infection.
Tat, the trans-activator of the Human Immunodeficiency Virus (HIV), activates the expression of genes under the control of the Long Terminal Repeat through an RNA target TAR (trans-activator response). Tat binds to the TAR RNA as a complex with Cyclin T1 and CDK9 to activate transcription. Once in the cytoplasm, the TAR RNA, located at the 5' end of all HIV mRNAs associates with other cellular factors to control the translation of HIV proteins. The translation of TAR-containing mRNAs can be inhibited by the interferon-induced protein kinase PKR and activated by the TAR RNA binding protein, TRBP. TRBP activates the HIV-1 translation by inhibiting PKR, by releasing a translation block due to TAR, and by preventing the PKR activator, PACT to activate PKR. All these mechanisms contribute to enhanced viral replication.
HIV gene expression and replication can be inhibited by RNA-based technologies like antisense nucleotides, ribozymes (Rz) and RNA interference (RNAi). Recent data show that TRBP is part of the RNA-induced silencing complex (RISC) that mediates RNAi, which suggests a crosstalk between HIV gene expression, control of PKR regulation and RNAi pathways.
Our research topics are:
1. HIV- host cell molecular interactions in the regulation of viral translation in lymphocytes and in astrocytes: Lymphocytes express TRBP in sufficient amount to allow HIV translation, whereas astrocytes restrict the translation of HIV mRNAs due to a limiting amount of TRBP. We study the mechanism by which a limiting amount of TRBP restricts HIV replication in astrocytes. We study the regulation of TRBP expression in astrocytes compared to lymphocytes.
2. Targeting viral and cellular factors involved in HIV expression to decrease viral replication: We use RNAi and improved forms of ribozymes to specifically target HIV RNA and cellular factors involved in HIV expression and replication.
3. Exploration of innate cellular response mediated by RNA interference during HIV replication: We want to determine if the RNAi can be an innate cellular response in mammalian cells as it is in plants and lower eukaryotes. Using HIV infection as a model, we explore the role of the RISC components during HIV infection.
4. Function of TRBP-Dicer interaction in RNA interference: TRBP and Dicer belong to the RISC and participate to the RNAi mechanism. We study their RNA binding activity to small RNAs and the mechanism of their interaction.
5. Crosstalk between the PKR activation and the RNAi pathways. Ribonucleoprotein complexes have multiple roles in a number of normal and pathogenic cellular mechanisms. They can influence pathways such as cell growth and cancer, development, reaction to pathogens and many others. Several RNA binding proteins like TRBP and PACT act in different complexes and pathways. We attempt to elucidate the mechanisms that trigger their involvement in PKR activation or repression, and in RNAi.
Selected Recent Publications
Daher, A., Laraki, G., Singh, M., Melendez-Peña, C., Bannwarth, S., Peters, A. H. F. M., Meurs, E. F., Braun, R. E., Patel R. C., and Gatignol A.. "TRBP control of PACT-induced phosphorylation of PKR is reversed by stress." Mol. Cell. Biol. 2009, 29: In press.
Laraki, G., Clerzius, G., Daher, A., Melendez-Peña, C., Daniels, S. and Gatignol, A. "Interactions between the double-stranded RNA-binding proteins TRBP and PACT define the Medipal domain that mediates protein-protein interactions." RNA Biol. 2008. 5:92-103.
Christensen, H. S., Daher, A., Soye, K. J., Frankel, L. B., Alexander M. R., Lainé S., Bannwarth, S., Ong, C. L., Chung, S. W. L., Campbell, S. M., Purcell, D. F. J. and Gatignol A. "Small interfering RNAs against the TAR RNA Binding Protein, TRBP, a Dicer cofactor, inhibit Human Immunodeficiency Virus type 1 long terminal repeat expression and viral production." J. Virol. 2007, 81:5121-5131.
Gatignol, A. "Transcription of HIV: Tat and cellular chromatin. In: Advances in Pharmacology, HIV-1: Molecular Biology and Pathogenesis: Viral mechanisms. Transcription of HIV: Tat and cellular chromatin. Publisher Elsevier. Ed. K.-T. Jeang, 2007, 55:137-159.
Bannwarth, S., Lainé, S., Daher A., Grandvaux, N., Clerzius, G., LeBlanc, A. C., Hiscott, J. and Gatignol, A. "Cell specific regulation of TRBP1 promoter by NF-Y transcription factor in lymphocytes and astrocytes." J. Mol. Biol. 2006, 355:898-910.
Gatignol, A., Lainé, S., and Clerzius, G. "Dual role of TRBP in HIV replication and RNA interference: viral diversion of a cellular pathway or evasion from antiviral immunity?" Retrovirology. 2005, 2:65.
Mouland, A. J., Heveker, N., and Gatignol, A. "Virus-cell interactions." In: Encyclopedia of Molecular Cell Biology and Molecular Medicine, 2d edition (2005). Publisher, Wiley-VCH Verlag, GmbH & Co. KgaA, Weinheim, Germany. Editor, R. A. Meyers. Vol. 15, pp. 423-484.
Haase, A. D., Jaskiewicz, L., Zhang, H., Lainé S., Sack R., Gatignol, A., and Filipowicz, W. "TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing." EMBO Rep. 2005, 6:961-967.
Ong CL, Thorpe JC, Gorry PR, Bannwarth S, Jaworowski A, Howard JL, Chung S, Campbell S, Christensen HS, Clerzius G, Mouland AJ, Gatignol A, and Purcell DFJ. "Low TRBP levels support an innate Human Immunodeficiency Virus type 1 resistance in astrocytes by enhancing the PKR antiviral response." J. Virol. 2005, 79:12763-12772.
Bannwarth S. and Gatignol A. "HIV-1 TAR RNA: the target of molecular interactions between the virus and its host." Curr. HIV Res. 2005, 3:61-71.
other publications here (author: Gatignol, A)
Lady Davis Institute for Medical Research
affiliated to McGill AIDS Centre and Molecular Oncology Group