Victor DeFilippis is an assistant scientist at the Vaccine and Gene Therapy Institute. After receiving his bachelor's degree from the University of Montana he received a Master's degree in Biology from Wayne State University. He completed his Ph.D. examining virus evolution at the University of California, Irvine. He conducted his postdoctoral work at the Vaccine and Gene Therapy Institute of OHSU.
Research in Dr. DeFilippis’ laboratory focuses on the biology of virus-host interactions especially with regard to innate immune and inflammatory responses to infection. In particular, he is interested in 1) The cellular recognition of virus-associated molecules that triggers cellular synthesis and secretion of antiviral and proinflammatory cytokines; 2) The evasion of innate antiviral activity by viruses; and 3) Therapeutic manipulation of innate and inflammatory responses to block virus replication and enhance vaccine immunogenicity. The laboratory employs traditional techniques of cellular and molecular biology and animal models as well as the tools of systems biology and functional genomics.
Specific foci of inquiry include the following:
1) Discovery and characterization of novel immunostimulatory compounds
The host innate immune response can be highly effective in both preventing replication of phylogenetically diverse viral pathogens but also in enhancing the initiation and establishment of adaptive immune responses. In light of this we employ high throughput screening strategies to identify novel small molecules capable of triggering specifically defined innate cellular signaling pathways and associated phenotypes. Ultimately the purpose of this research is to discover, characterize, and develop therapeutic compounds that can be used to both inhibit the spread of novel and other viral diseases as well as enhance the immunogenicity of vaccines.
2) Antiviral responses to Chikungunya virus
Chikungunya virus (CHIKV) is an RNA virus that is transmitted by mosquitoes and associated with the development of severe and persistent arthritis. In recent years CHIKV has experienced an explosive reemergence that has now entered the mainland United States. Unfortunately, comparatively little is known regarding the molecular biology of CHIKV-host cell interactions. Our work involves both characterization of the host pathogen-sensing apparatus involved in CHIKV detection and the cellular physiological state triggered by CHIKV infection as well as identification of strategies to block virus replication. This research employs cellular and transgenic murine models of CHIKV infection, immunity, and pathogenesis and relies on techniques such as RNA interference (in vitro and in vivo), directed viral mutation and ectopic gene insertion, proteomics, and transcriptomics.
3) Induction and evasion of innate immune responses by primate cytomegaloviruses
Human cytomegalovirus (HCMV) is a member of the herpesvirus family that infects human hosts persistently and is responsible for disease in numerous tissue types especially in immunocompromised patients. HCMV is also the leading infectious cause of birth defects. Exposure of human cells to HCMV triggers strong innate immune responses that include secretion of type I interferon and proinflammatory cytokines such as interleukin 1 β (IL-1β). We are focused on characterizing the cellular receptors and pathways triggered by cytomegalovirus infection that lead to induction of these innate responses. We are also investigating the immunostimulatory virus-associated molecules (nucleic acids, proteins) that are detected by infected cells that stimulate these pathways. This work involves microarray and quantitative PCR based analysis of virus-induced gene expression, RNA interference-mediated gene expression knockdown, lentivirus-dependent stable cell line construction, and promoter activation analysis using reporter cells.
Areas of interest
- Activation and evasion of innate immune responses by viral pathogens
Hirsch AJ, Smith JL, Haese NN, Broeckel RM, Parkins CJ, Kreklywich C, DeFilippis VR, Denton M, Smith PP, Messer WB, Colgin LM, Ducore RM, Grigsby PL, Hennebold JD, Swanson T, Legasse AW, Axthelm MK, MacAllister R, Wiley CA, Nelson JA, Streblow DN. Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues. PLoS Pathog. 2017 Mar 9;13(3):e1006219. doi: 0.1371/journal.ppat.1006219. [PMID: 28278237]
Greene TT, Tokuyama M, Knudsen GM, Kunz M, Lin J, Greninger AL, DeFilippis VR, DeRisi JL, Raulet DH, Coscoy L. A Herpesviral induction of RAE-1 NKG2D ligand expression occurs through release of HDAC mediated repression. Elife. 2016 Nov 22;5. pii: e14749. doi: 10.7554/eLife.14749. [PMID: 27874833]
Uhrlaub JL, Pulko V, DeFilippis VR, Broeckel R, Streblow DN, Coleman GD, Park BS, Lindo JF, Vickers I, Anzinger JJ, Nikolich-Žugich J. Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus. PLoS Pathog. 2016 Oct 13;12(10):e1005891. doi: 10.1371/journal.ppat.1005891. eCollection 2016 Oct. [PMID: 27736984]
Sali TM, Pryke KM, Abraham J, Liu A, Archer I, Broeckel R, Staverosky JA, Smith JL, Al-Shammari A, Amsler L, Sheridan K, Nilsen A, Streblow DN, DeFilippis VR. Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. PLoS Pathog. 2015 Dec 8;11(12):e1005324. doi: 10.1371/journal.ppat.1005324. eCollection 2015 Dec. [PMID: 26646986]
- "Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology." Nature Communications In: , Vol. 9, No. 1, 263, 01.12.2018.
- "Emerging alphaviruses are sensitive to cellular states induced by a novel small-molecule agonist of the STING pathway." Journal of Virology In: , Vol. 92, No. 6, e01913-17, 01.03.2018.
- "A novel agonist of the trif pathway induces a cellular state refractory to replication of Zika, Chikungunya, and dengue viruses." mBio In: , Vol. 8, No. 3, e00452-17, 01.05.2017.
- "Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues." PLoS Pathogens In: , Vol. 13, No. 3, e1006219, 01.03.2017.
- "High-throughput screening for identification of novel innate immune activators." Methods in Molecular Biology. Vol. 1656 Humana Press Inc., 2017. p. 183-193 (Methods in Molecular Biology; Vol. 1656).
- "A herpesviral induction of RAE-1 NKG2D ligand expression occurs through release of HDAC mediated repression." eLife In: , Vol. 5, No. NOVEMBER2016, e14749, 22.11.2016.
- "Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus." PLoS Pathogens In: , Vol. 12, No. 10, e1005891, 01.10.2016.
- "Human Cytomegalovirus miR-UL112-3p Targets TLR2 and Modulates the TLR2/IRAK1/NFκB Signaling Pathway." PLoS Pathogens In: , Vol. 11, No. 5, e1004881, 01.05.2015.
- "Varicella Viruses Inhibit Interferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms." PLoS Pathogens In: , Vol. 11, No. 5, e1004901, 01.05.2015.
- "The ORF61 protein encoded by Simian varicella virus and Varicella-zoster virus inhibits NF-κB signaling by interfering with IκBα degradation." Journal of Virology In: , Vol. 89, No. 17, 2015, p. 8687-8700.
- "Sequence-specific modifications enhance the broad-spectrum antiviral response activated by RIG-I agonists." Journal of Virology In: , Vol. 89, No. 15, 2015, p. 8011-8025.
- "Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses." PLoS Pathogens In: , Vol. 11, No. 12, e1005324, 2015.
- "Cytomegalovirus pp65 limits dissemination but is dispensable for persistence." Journal of Clinical Investigation In: , Vol. 124, No. 5, 2014, p. 1928-1944.
- "The tiers and dimensions of evasion of the type i interferon response by human cytomegalovirus." Journal of Molecular Biology In: , Vol. 425, No. 24, 13.12.2013, p. 4857-4871.
- "Chikungunya Virus Infection Results in Higher and Persistent Viral Replication in Aged Rhesus Macaques Due to Defects in Anti-Viral Immunity." PLoS Neglected Tropical Diseases In: , Vol. 7, No. 7, e2343, 07.2013.
- "The inflammasome as a target of modulation by DNA viruses." Future Virology In: , Vol. 8, No. 4, 2013, p. 357-370.
- "Association of human papillomavirus type 31 variants with risk of cervical intraepithelial neoplasia grades 2-3." International Journal of Cancer In: , Vol. 131, No. 10, 15.11.2012, p. 2300-2307.
- "Motif-optimized subtype A HIV envelope-based DNA vaccines rapidly elicit neutralizing antibodies when delivered sequentially." Vaccine In: , Vol. 30, No. 37, 10.08.2012, p. 5519-5526.
- "Viral interferon regulatory factors are critical for delay of the host immune response against rhesus macaque rhadinovirus infection." Journal of Virology In: , Vol. 86, No. 5, 03.2012, p. 2769-2779.
- "Ebola virion attachment and entry into human Macrophages profoundly effects early cellular gene expression." PLoS Neglected Tropical Diseases In: , Vol. 5, No. 10, e1359, 10.2011.
- "IL-6 in human cytomegalovirus secretome promotes angiogenesis and survival of endothelial cells through the stimulation of survivin." Blood In: , Vol. 117, No. 1, 06.01.2011, p. 352-361.
- "Chikungunya virus induces IPS-1-dependent innate immune activation and protein kinase R-independent translational shutoff." Journal of Virology In: , Vol. 85, No. 1, 01.2011, p. 606-620.
- "Activation of the interferon response by human cytomegalovirus occurs via cytoplasmic double-stranded DNA but not glycoprotein B." Journal of Virology In: , Vol. 84, No. 17, 09.2010, p. 8913-8925.
- "Viral hijacking of the host ubiquitin system to evade interferon responses." Current Opinion in Microbiology In: , Vol. 13, No. 4, 08.2010, p. 517-523.
- "Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1." Journal of Virology In: , Vol. 84, No. 1, 01.2010, p. 565-598.
- "Differential ligand binding to a human cytomegalovirus chemokine receptor determines cell type-specific motility." PLoS Pathogens In: , Vol. 5, No. 2, e1000304, 02.2009.
- "The role of angiogenic and wound repair factors during CMV-accelerated transplant vascular sclerosis in rat cardiac transplants." American Journal of Transplantation In: , Vol. 8, No. 2, 02.2008, p. 277-287.
- "Cytomegalovirus immune evasion." Current Topics in Microbiology and Immunology In: , Vol. 325, 2008, p. 333-359.
- "West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis." Journal of Virology In: , Vol. 81, No. 20, 10.2007, p. 10849-10860.
- "Rat cytomegalovirus gene expression in cardiac allograft recipients is tissue specific and does not parallel the profiles detected in vitro." Journal of Virology In: , Vol. 81, No. 8, 04.2007, p. 3816-3826.