Professor;
Molecular Biology/Virology
Transcriptional control of cytokine and chemokine gene expression during human retrovirus pathogenesis
Accepting graduate students
Professor/Director
Molecular Oncology
Lady Davis Institute, Room 528
3755 Côte-Ste-Catherine Road
Montreal, QC H3T 1E2
Tel: (514) 340-8260 x.5265
Fax: (514) 340-7576
john [dot] hiscott [at] mcgill [dot] ca (Email)
Website: www.johnhiscottlab.ca
Research Orientations
Our research program is focused on the molecular interactions between several human pathogenic viruses and the host cytokine respone to virus infection. These studies impact on diverse areas of research including infectious disease, viral oncology and AIDS. Below I outline our studies in several interrelated areas of research.
A) Activation of the Interferon Antiviral Defense Pathway by IRF Transcription Factors
Virus infection of susceptible cells activates multiple signaling pathways that orchestrate the activation of interferons and cytokines involved in the antiviral and innate immune response. Central to cytokine activation mechanisms are the NF-kappaB and IRF transcription factors that coordinately control the transcriptional activation of multiple cytokines.
Studies over the past five years have detailed the mechanisms of interferon (IFN) and RANTES activation by IRF-3 and IRF-7, as well as NF- kappaB, using numerous biochemical and molecular approaches. Our hypothesis is that IRF-3 and IRF-7 are central to the activation of the antiviral cascade and that IFN production is critical to the mobilization of the innate and adaptive immune response. Since specific subpopulations of dendritic cells have been characterized as major IFN producers, we argue that IRF in these cells will be essential to the induction of the multiple Type 1 IFN genes.
Furthermore, recent studies indicate that defects in the interferon antiviral cascade in many distinct tumor types may underlie the capacity of replication competent viruses such as Vesicular Stomatitis Virus and Reovirus to selectively multiply and destroy tumor cells. This promising area of cancer therapy is one of our priorities in future studies. Our research goals therefore are to further characterize the molecular details of IRF activation, role of IRF members in the IFN response in dendritic cells and to analyze in detail potential defects in the IFN pathway that may predispose cancer cells to the oncolytic effects VSV. (Funded by CIHR).
B) The Role of IRF-4 Transcription Factor in HTLV-1 induced T cell Leukemogenesis
The human T cell lymphotropic virus (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL), an aggressive and often fatal leukemia of CD4+ T lymphocytes. The oncogenic potential of HTLV-I resides in the viral Tax protein which disrupts host signaling and transcriptional regulation via protein-protein interactions.
One of the targets of Tax is the NF-kappaB/IkB factors which control inducible immune and growth regulatory gene transcription. These molecular events culminate in transcriptional deregulation in HTLV-1 infected cells that predisposes to ATL development.
Recently, a lymphoid specific IRF - IRF-4 - was shown to be constitutively expressed in all ATL patient cells and in HTLV-1 infected cell lines. The hypothesis that Tax oncoprotein-induced IRF-4 expression is an important cellular target in HTLV-1-induced T cell leukemogenesis is currently being investigated. We have demonstrated that coordinate regulation by the NF-kappaB and NF-AT pathways is responsible for IRF-4 expression in HTLV-I infected, ATL-derived cells. The involvement of Tax in chronic activation of these cascades during HTLV-I infection and ATL development will be explored and the involvement of a novel lymphoid-restricted IkappaB kinase epsilon (IKKepsilon) will be examined. IRF-4 production in turn negatively regulates a network of host genes, some of which are crucial for T cell leukemogenesis. Based on co-expression studies, cDNA array and yeast two- hybrid analyses, regulatory targets involved in cell cycle progression (cyclin B1), G protein coupled signaling (RhoA) and ligand induced apoptosis (TRAIL) have been identified. The molecular basis of IRF-4 inhibition of gene expression will be investigated. (Funded by NCIC).
C) Analysis of transcriptional mechanisms regulating African, Asian and North American HIV-1 Subtypes
The major group of HIV-1 viruses that comprise the current global pandemic have diversified during their worldwide spread and may be divided into at least 10 distinct subtypes or clades. Subtype B predominates in North America and Europe; subtype E predominates in southeast Asia and subtype C predominates in sub-Saharan Africa. Currently, HIV-E and HIV-C are the most prevalent HIV-1 subtypes in the world.
Analysis of the LTR repeats of HIV-1E and HIV-1C isolates have identified subtype specific differences in activation in response to NF-kappaB, NFAT and viral Tat. Functional distinctions in promoter architecture between HIV subtypes raises the possibility that regulatory divergence has occurred amongst the subtypes of HIV-1 that may explain differences in virus replication and transmission. The related events of transcriptional activation by host transcription factors and regulation of transcriptional initiation and elongation by Tat/TAR host protein interactions provide a complex and essential mechanism to regulate HIV-1 transcription.
It is our hypothesis that distinct interactions between host signaling pathways and the enhancer regions of different HIV-1 subtypes, together with subtype specific interactions between Tat, TAR and cellular proteins, modulate the efficiency of HIV-1 clade specific gene transcription with effects on viral replication in a variety of different cell types.
We are currently investigating the alterations in the molecular architecture of HIV-1 enhancer domains and clade-specific regulation by distinct Tat/TAR interactions. Transcriptional and replication efficiencies of different clade isolates will be investigated in different T and monocytic cell types and the functional details of clade-specific promoter activation will be determined by genomic footprinting and protein-protein interactions. (Funded by the CIHR Group in HIV Pathogenesis).
Selected Publications
Harris, J, Sharma S, Sun Q, Oliere S, Lin R, Hiscott J, Grandvaux N. "Nuclear accumulation of c-Rel following C-terminal phosphorylation by TBK1/IKKε." J. Immunol. 177: 2527-2535 (2006).
Lin R, Lacoste J, Nakhaei P, Sun Q, Paz S, Yang L, Julkunen I, Meurs E, Hiscott J. "Dissociation of a MAVS/IPS/VISA/Cardif and IKKepsilon complex from the mitochondrial outer membrane by hepatitis C virus NS3-4A proteolytic cleavage." J. Virol. 80: 6072-6083 (2006).
Arguello M, Paz S, Hernandez E, Corriveau-Bourque C, Fawaz L, Hiscott J, Lin R. "LTA4H expression in primary effusion lymphoma is regulated at the transcriptional level and leads to increased LTB4 production." J. Immunol. 176: 7051-7061 (2006).
Solis M, Wilkinson P, Romieu R, Hernandez E, Wainberg MA, Hiscott J. "Gene expression profiling of the host response to HIV-1 B, C or A/E infection in monocyte-derived dendritic cells." Virology 352: 86-99 (2006).
Cesaire R, Oliere S, Sharif-Askari E, Loignon M, Lezin A, Olindo S, Panelatti G, Kazanji M, Panasci L, Hiscott J. "Oncolytic activity of VSV in primary adult T cell leukemia." Oncogene 25: 349-358 (2006).
Lin R, Nakhaei P, Yang L, Sharif-Askari E, Julkunen I, Hiscott J. "Negative regulation of the RIG-I induced antiviral state by the ubiquitin editing protein A20." J. Biol. Chem. 281: 2095-2103 (2006).
Civas A, Genin P, Moran P, Lin R, Hiscott J. "Promoter organization of the interferon-A genes differentially affects virus-induced expression and responsiveness to TBK1 and IKKepsilon." J. Biol. Chem. 281: 4856-4866 (2006).
Hiscott J, Lin R, Nakhaei P, Paz S. "MasterCARD: a priceless link to innate immunity." Trends in Mol. Medicine 12: 53-56 (2006).
Breiman A, Grandvaux N, Lin R, Ottone C., Akira S, Yoneyama M, Fujita T, Hiscott J, Meurs E. "Inhibition of RIG-I-dependent IFN signaling pathway during hepatitis C expression and restoration of signaling by IKKepsilon." J. Virol. 79: 3969-3978 (2005).
Desfosses Y, Solis M, Sun Q, Grandvaux N, vanLint C, Burny A, Gatignol A, Wainberg M, Lin R, Hiscott J. "Regulation of HIV-1 gene expression by clade specific Tat proteins." J. Virol. 79: 9180-9191 (2005).
Gautier G, Humbert M, Deauvieau F, Seuiller M, Hiscott J, Bates EEM, Trinchieri G, Caux C, Garrone P. "A Type 1 interferon autocrin/paracrine loop is involved in Toll-like receptor induced IL12p70 secretion in dendritic cells." J. Exp. Med. 201: 1435-1443 (2005).
Hiscott J, Lin R. "IRF-3 releases its inhibitions." Structure 13: 1235-1236 (2005).
tenOever B, Sharma S, Zou W, Sun Q, Grandvaux N, Julkunen I, Hemmi H, Yamamoto M, Akira S, Yeh W, Lin R, Hiscott J. "Activation of TBK1 and IKK kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity." J. Virol. 78: 10636-10649 (2004).
Hiscott J. "Another detour on the Toll road to the interferon antiviral response." Nature Struct. & Mol. Biol. 4: 1028-1030 (2004).
Sharma S, tenOever B, Grandvaux N, Zhou G, Lin R, Hiscott J. "Triggering the interferon antiviral response through an IKK-related pathway." Science 300: 1148-1151 (2003).
Stojdl D, Lichty B, tenOever B, Knowles S, Marius R, Reynard J, Ruoso P, Poloquin L, Atkins H, Brown EG, Durbin R, Durbin J, Hiscott J, Bell JC. "Oncolytic VSV strains with defects in the shutdown of innate immunity are potent systemic anti-cancer agents." Cancer Cell 4: 263-275 (2003).
Sharma S, Grandvaux N, Mamane Y, Genin P, Azimi N, Waldmann T, Hiscott J. "Regulation of IRF-4 expression in HTLV-1 infected leukemia cells." J. Immunol. 169: 3120-3130 (2002).
Duguay D, Mercier F, Stagg J, Servant M, Lin R, Galipeau J, Bramson J, Hiscott J. "In vivo tumor suppressor function of IRF-3 in murine melanoma B16 cells." Cancer Res. 62: 5148-5152 (2002).
Mamane Y, Grandvaux N, Hernandez E, Sharma S, Innocente S, Lee JM, Azimi N, Lin R, Hiscott J. "Repression of IRF-4 target genes in HTLV-1 infection." Oncogene 21: 6751-6765 (2002).
Hiscott J, Kwon HJ, Genin P. "Hostile takeovers: viral appropriation of the NF-kB pathway." J. Clin. Invest. 107: 143-151 (2001).
Baetu T, Kwon HJ, Sharma S, Grandvaux N, Hiscott J. "Disruption of NF-kappaB signaling reveals a novel role for NF-kappaB in the regulation of TRAIL." J. Immunol. 167: 3164-3173 (2001).
Mamane Y, Sharma S, Petropoulos L, Lin R, Hiscott J. "Posttranslational regulation of IRF-4 activity by the immunophilin FKBP52." Immunity 12: 129-140 (2000).
Lin R, Genin P, Mamane Y, Hiscott J. "DNA binding specificity and association with CBP co-activator contribute to differential activation of type 1 interferon gene by IRF-3 and IRF-7." Mol. Cell. Biol. 20: 6342-6353 (2000).