Virus-cell interactions in the regulation of HIV expression and replication.
Virus-cell interactions laboratory
Lady Davis Institute for Medical Research
3999 Côte-Ste-Catherine Road
Montréal, QC H3T 1E2
Tel: (514) 340-8222 ext: 5284
Fax: (514) 340-7576
Accepting graduate students
Virus replication is the result of a co-evolution between the virus and its host. Viral proteins and RNAs use cellular components for their function and act on cellular mechanisms. In response, cellular pathways interfere with viruses, which result in helping or counteracting viral replication. We study the regulation of these mechanisms in the context of the Human Immunodeficiency Virus (HIV) infection. With the increasing efficacy of the treatments (1997 to present), HIV infection has become a chronic disease instead of a deadly disease, but there is still no cure. My lab applies fundamental knowledge in virus-cell interactions to address some remaining issues with HIV treated patients. We study the weak innate immune response to HIV and the viral persistence in specific cells, the interplay between RNA interference mechanisms and HIV in long-term infection and the search for compounds, which could be used in gene therapy to completely eliminate the virus:
1) Innate cell response to HIV infection: We characterize part of the innate cell response to HIV infection after interferon production. HIV has evolved to replicate in cells where this response is limited due to multiple cellular events. We have characterized the control of PKR activation by TRBP (a protein that binds the HIV TAR RNA), PACT (PKR activator) and ADAR1 during HIV replication. We continue with the elucidation of more mechanisms and the characterization of these regulations in patients with persistent infection.
2) Interactions between HIV and the RNA interference pathway. The RNA interference pathway has emerged as a major gene regulation pathway. We have contributed to the identification of TRBP as part of the basic complex necessary for its function in mammalian cells. We investigate the interplay between components of the RNA interference pathway and HIV RNA and proteins to determine how the modifications induced by the virus contribute to the pathogenicity.
3) Using RNA-based technologies to decrease HIV replication by gene therapy. The current therapies against HIV are treatments but not a cure. As soon as the treatment is stopped, a rebound of the viremy is observed. Therefore, it is a priority to develop treatments, which can potentially eliminate the virus or eliminate infected cells located in the so called “reservoir cells”. One example of a cured patient after transplantation of non-infectable stem cells shows that the modification of hematopoietic stem cells with RNA-based anti-HIV compounds by gene therapy should be feasible. We explore different compounds from small interfering RNAs to ribozymes to target the HIV RNA and the RNA of cellular factors required for its replication to reach a maximum inhibition of virus replication.
Selected Recent Publications:
1. Scarborough, R.J., Lévesque, M.V., Perreault, J.-P. and Gatignol, A. Design and evaluation of clinically relevant SOFA HDV Ribozymes targeting HIV RNA. Methods Mol. Biol. (In press, 2013).
2. Clerzius, G., Shaw, E., Daher, A., Burugu, S., Gélinas, J.-F., Ear, T., Sinck, L., Routy, J.-P., Mouland, A.J., Patel, R.C. and Gatignol, A. The PKR activator, PACT, becomes a PKR inhibitor during HIV replication. Retrovirology. 2013. 10:96.
3. Daniels, S. M., and Gatignol, A. The multiple functions of TRBP: at the hub of cell responses to viruses, stress and cancer. Microb. Mol. Biol. Rev. 2012, 76:652-666.
4. Gélinas, J.-F., Clerzius, G., Shaw, E., and Gatignol. A. ADAR1 enhancement of replication of RNA viruses via RNA editing and inhibition of PKR. J. Virol. 2011. 85:8460–8466.
5. Lainé, S., Scarborough, R.J., Lévesque, D., Didierlaurent, L., Soye, K.J., Mougel, M., Perreault, J.-P. and Gatignol, A. In vitro and in vivo cleavage of HIV-1 RNA by new SOFA-HDV ribozymes and their potential to inhibit viral replication. RNA Biol. 2011. 8:343-353.
6. Clerzius, G., Gélinas, J.-F. and Gatignol, A. Multiple levels of PKR inhibition during HIV-1 replication. Rev. Med. Virol. 2011. 21:42-53
7. Clerzius, G., Gélinas, J.-F., Daher, A., Bonnet, M., Meurs, E.F., and Gatignol, A. ADAR1 interacts with PKR during HIV infection of lymphocytes and contributes to viral replication. J. Virol. 2009. 83:10119-10128.
8. Daniels, S.M., Melendez-Peña, C.E., Scarborough, R.J., Daher, A., Christensen, H.S., El Far, M., Purcell, D.F., Lainé, S. and Gatignol, A. Characterization of the TRBP domain required for Dicer interaction and function in RNA interference. BMC Mol. Biol. 2009.
9. 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, 29:254-265.
Other publications at:
author: Gatignol, A
Link to Lady Davis Institute for Medical Research:
Link to the department of Medicine, division of Experimental Medicine:
affiliated to: McGill AIDS Centre and FRQ-S “Réseau SIDA et Maladies Infectieuses”