Laboratory of Dr. John Hiscott
The goals of the research program of Dr. John Hiscott are two-fold:
Three different areas of research are currently being pursued:
- to understand the early events involved in the host response to human pathogenic virus infection; and
- to use our knowledge of virus-host interactions to develop novel anti-cancer oncolytic vaccines.
Three different areas of research are currently being pursued:
- Molecular interactions and signaling events that regulate the host antiviral immune response to virus infection, mediated through TLR dependent and RIG-I dependent signaling pathways - Interferon gene activation.
- Development of oncolytic vaccines as cancer therapeutics. Investigation of promising combination therapies to improve the spectra of oncolytic vaccines as cancer therapeutics for solid and hematological malignancies.
- Pathogenesis and gene expression in human retrovirus infection: analysis of the biochemical and genetic events that determine whether individuals infected with human T cell leukemia virus (HTLV-1) progress to leukemic disease or develop HTLV-1 associated myelopathy (HAM/TSP).
Project 1. Molecular interactions regulating antiviral signaling
Figure 1
Upon recognition of specific molecular components of viruses, the host cell activates multiple signaling cascades that stimulate an innate antiviral response, resulting in the disruption of viral replication, and the mobilization of the adaptive arm of the immune system. Central to the host antiviral response is the production of type I interferons (IFNs), a large family of multifunctional immunoregulatory proteins. Multiple Toll-like receptor (TLR)-dependent (TLR-3, -4, -7 and 9) and independent (RIG-I and Mda5) pathways are involved in the cell specific regulation of Type I IFNs. Coordination of downstream activation for both TLR-dependent and RIG-I-dependent pathways causes divergent signals at the level of kinase activity – with IKKa/IKKb promoting activation of NF-kB and inflammatory cytokine production, and TBK1/IKKe driving the antiviral arm of innate immunity via IRF3 and IRF7 stimulation (Figure 1). We are investigating the molecular interactions that activate antiviral signaling in response to two serious human pathogens:
1) Dengue virus a mosquito born virus responsible for an acute febrile illness and more serious complications including Dengue hemorrhagic fever; as such Dengue represents a major global health concern for more the 3 billion people in tropical areas of the world. At present, no effective vaccine or antiviral drugs exist to combat Dengue virus. A major objective of this project is to develop small molecules to trigger antiviral pathways that intrinsically combat infection and instruct adaptive immune response.
2) HTLV-1 (Human T Cell Leukemia Virus 1) is a human retrovirus that is the causative agent of Adult T Cell Leukemia (ATL), an aggressive and fatal leukemia. HTLV-1 is also associated with a neurological demyelinating disease, tropical spastic paraparesis (HAM/TSP).
1) Dengue virus a mosquito born virus responsible for an acute febrile illness and more serious complications including Dengue hemorrhagic fever; as such Dengue represents a major global health concern for more the 3 billion people in tropical areas of the world. At present, no effective vaccine or antiviral drugs exist to combat Dengue virus. A major objective of this project is to develop small molecules to trigger antiviral pathways that intrinsically combat infection and instruct adaptive immune response.
2) HTLV-1 (Human T Cell Leukemia Virus 1) is a human retrovirus that is the causative agent of Adult T Cell Leukemia (ATL), an aggressive and fatal leukemia. HTLV-1 is also associated with a neurological demyelinating disease, tropical spastic paraparesis (HAM/TSP).
Project 2. Development of oncolytic vaccines for cancer treatment
Figure 2
An ideal cancer therapeutic will selectively kill malignant cells using a multi-pronged approach, while leaving normal tissues intact. The current standards of cancer care - chemotherapy and radiation therapy – often fall short of this goal. Thus, it is imperative to use new knowledge of the molecular biology of cancer to generate novel therapeutics that specifically target cancer cells. Several new avenues of research have moved to pre-clinical and clinic trials with the design of novel biotherapeutics such as monoclonal antibodies, immunotherapies and oncolytic viruses (OV). These strategies selectively exploit genetic defects commonly found in tumor cells and represent promising new treatments for a range of human cancers. Current projects seek to evaluate the efficiency of OV combination therapies in chronic lymphocytic leukemia (CLL) and prostate cancer models using 1) the combination of OV and anti-apoptotic Bcl-2 inhibitors in CLL, and 2) the combination of VSV and histone deacetylase inhibitors in androgen-independent prostate cancer (Figure 2).
Contact Information
John Hiscott, Ph.D.
Full Member
Vaccine & Gene Therapy Institute
9801 SW Discovery Way
Port St. Lucie, FL 34987
Tel: (772)345-5694
Fax: (772)345-0625
Email: [email protected]
Lab Members
Tel: (772)345-5701
Fax: (772)345-0625
Zhong He, PhD, [email protected]
Vladimir Beljanski [email protected]
Carmen Nichols, PhD, [email protected]
David Olagnier, PhD, [email protected]
Publications
Full Member
Vaccine & Gene Therapy Institute
9801 SW Discovery Way
Port St. Lucie, FL 34987
Tel: (772)345-5694
Fax: (772)345-0625
Email: [email protected]
Lab Members
Tel: (772)345-5701
Fax: (772)345-0625
Zhong He, PhD, [email protected]
Vladimir Beljanski [email protected]
Carmen Nichols, PhD, [email protected]
David Olagnier, PhD, [email protected]
Publications
Select Publications (from a total of 220)
Paz S, Vilasco M, Arguello M, Werden S, Lin R, Meurs E, Hiscott J.A functional C-terminal TRAF3 binding site in MAVS participates in positive and negative regulation of the interferon antiviral response. Cell Research (2011).
Leveille S, Goulet ML,Samuel S, Hiscott J. Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy. Cancer Gene Therapy (2011).
Solis M, Nakhaei P, Jalalirad M, Lacoste J, Douville R, Arguello M, Laughrea M, Hiscott J. RIG-I dependent antiviral signaling is inhibited during de novo HIV-1 infection by protease-mediated sequestration of RIG-I. J. Virol. 85: 1224-1236 (2011).
Paz S, Hiscott J. CuRTAiling IRF signaling with the E3 ligase RAUL. Immunity 33: 833-835 (2010).
Olière S, Hernandez E, Lézin A, Nguyen TL, Arguello M, Wilkinson P, Sekaly R, Césaire R and Hiscott J. HTLV-1 evades antiviral immunity via upregulation of SOCS1 PLoS Pathogens, 6: e1001177 (2010).
Samuel S, TumilasciV, Oliere S, NguyênT L-A, ShamyA, Bell J and Hiscott J. VSV oncolysis in combination with the BCL-2 inhibitor GX15-070 overcomes apoptotic resistance in CLL cells. Mol. Therapy, 18: 2094-2103 (2010).
Goubau D, Romieu-Mourez R, Solis M, Hernandez E, Mesplede T, Lin R, Leaman D, Hiscott J. Transcriptional re-programming of human macrophages reveals distinct apoptotic and anti-tumor functions of IRF-3 and IRF-7. Eur. J. Immunol. 39 : 527-540 (2009).
Nakhaei P, MespledeT, Sun Q, SolisM, YangL, ChuangT-H, WareCF, LinR, Hiscott J.The E3 Ubiquitin ligase TRIAD3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation PLoS Pathogens 5(11):e1000650. Epub 2009.
Nguyen L-A, Abdelbary H, Arguello M, Breitbach C, Leveille S, Yasmeen A, Bismar T, Falls T, Werier J, Bell JC, Hiscott J. Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis Proc. Natl. Acad. Sci. USA. 105: 14981-14986 (2008).
Zhao TJ, Yang L, Sun Q, Arguello M, Ballard DW, Hiscott J, Lin R. The NEMO/IKKg adapter bridges NF-kB and IRF signaling pathways. Nature Immunology, 8: 592-600 (2007).
Paz S, Vilasco M, Arguello M, Werden S, Lin R, Meurs E, Hiscott J.A functional C-terminal TRAF3 binding site in MAVS participates in positive and negative regulation of the interferon antiviral response. Cell Research (2011).
Leveille S, Goulet ML,Samuel S, Hiscott J. Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy. Cancer Gene Therapy (2011).
Solis M, Nakhaei P, Jalalirad M, Lacoste J, Douville R, Arguello M, Laughrea M, Hiscott J. RIG-I dependent antiviral signaling is inhibited during de novo HIV-1 infection by protease-mediated sequestration of RIG-I. J. Virol. 85: 1224-1236 (2011).
Paz S, Hiscott J. CuRTAiling IRF signaling with the E3 ligase RAUL. Immunity 33: 833-835 (2010).
Olière S, Hernandez E, Lézin A, Nguyen TL, Arguello M, Wilkinson P, Sekaly R, Césaire R and Hiscott J. HTLV-1 evades antiviral immunity via upregulation of SOCS1 PLoS Pathogens, 6: e1001177 (2010).
Samuel S, TumilasciV, Oliere S, NguyênT L-A, ShamyA, Bell J and Hiscott J. VSV oncolysis in combination with the BCL-2 inhibitor GX15-070 overcomes apoptotic resistance in CLL cells. Mol. Therapy, 18: 2094-2103 (2010).
Goubau D, Romieu-Mourez R, Solis M, Hernandez E, Mesplede T, Lin R, Leaman D, Hiscott J. Transcriptional re-programming of human macrophages reveals distinct apoptotic and anti-tumor functions of IRF-3 and IRF-7. Eur. J. Immunol. 39 : 527-540 (2009).
Nakhaei P, MespledeT, Sun Q, SolisM, YangL, ChuangT-H, WareCF, LinR, Hiscott J.The E3 Ubiquitin ligase TRIAD3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation PLoS Pathogens 5(11):e1000650. Epub 2009.
Nguyen L-A, Abdelbary H, Arguello M, Breitbach C, Leveille S, Yasmeen A, Bismar T, Falls T, Werier J, Bell JC, Hiscott J. Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis Proc. Natl. Acad. Sci. USA. 105: 14981-14986 (2008).
Zhao TJ, Yang L, Sun Q, Arguello M, Ballard DW, Hiscott J, Lin R. The NEMO/IKKg adapter bridges NF-kB and IRF signaling pathways. Nature Immunology, 8: 592-600 (2007).