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 detection of virus-associated molecules that triggers host 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 processes to block virus replication and pathogenesis. The laboratory employs traditional techniques of cellular and molecular biology as well as the tools of systems biology and functional genomics. Specific foci of inquiry include the following:
1) Induction and evasion of the innate antiviral response by Chikungunya virus
Chikungunya virus (CHIKV) is an acute RNA virus and a member of the Alphavirus genus that is transmitted by mosquitoes and is associated with the development of severe and persistent arthritis. In recent years CHIKV has experienced an explosive reemergence due to the evolution of a new strain capable of being transmitted via anthropophillic mosquito species. Unfortunately, comparatively little is known regarding the molecular biology of CHIKV-host cell interactions. The focus of this work is a detailed characterization of the host pathogen-sensing apparatus involved in CHIKV detection and the cellular physiological state triggered by CHIKV infection. This includes activation of transcription factors responsible for expression of numerous antiviral molecules but also the rapid shutoff of cellular (but not viral) protein translation. Furthermore, we are also interested in characterizing the cellular and molecular bases of CHIKV-associated inflammatory responses in the arthritic joint to identify therapeutic targets that may alleviate disease. This work 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.
2) Discovery of broad spectrum antiviral compounds
Zoonotic and emerging viruses represent a perpetual threat to human populations worldwide. This is especially true with regard to arthropod-borne pathogens that are increasing in response to 1) Changing patterns of mosquito vector distribution and abundance caused by climate change; and 2) Increased vector-human contact following human encroachment into undeveloped areas. Unfortunately, the unknown and unpredictable nature of these agents renders them extremely difficult to diagnose and treat. Fortuitously, the host innate immune response can be highly effective in preventing or impairing replication of phylogenetically diverse viral pathogens. In light of this we have employed a high throughput screening platform to identify a pool of small bioactive lead molecules that trigger antiviral innate immune responses in mammalian cells. Ultimately the purpose of this research is to discover, characterize, and develop therapeutic compounds that can be used to inhibit the spread of spontaneously emerging and, in many cases, novel viral diseases.
3) Induction and evasion of innate and inflammatory 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.
4) Molecular evolution and population genetics of oncogenic human papillomaviruses
Human papillomaviruses (HPVs) are sexually transmitted pathogens that are the etiologic agents of nearly all cervical cancers. HPVs are represented by over one hundred phylogenetically distinct types that have existed with our species since the mammalian radiation. Intriguingly, although different types exhibit generally similar mechanisms of transmission and replication, the strength and quality of natural selective forces shaping their diversification vary greatly. These different paths of evolutionary change can have strong implications for the design and efficacy of vaccines directed against oncogenic HPVs. This work aims to evaluate and compare patterns of molecular evolution of protein coding genes (especially oncogenes) between HPV types and to reconstruct the demographic histories of HPV populations using phylogenetic and probabilistic modeling.
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.
1: Pissani F, Malherbe DC, Robins H, DeFilippis VR, Park B, Sellhorn G, Stamatatos L, Overbaugh J, Haigwood NL. Motif-optimized subtype A HIV envelope-based DNA vaccines rapidly elicit neutralizing antibodies when delivered sequentially. Vaccine. 2012 Aug 10; 30(37): 5519-26. PMCID: PMC3447634
2: Robinson BA, O'Connor MA, Li H, Engelmann F, Poland B, Grant R, DeFilippis VR, Estep RD, Axthelm MK, Messaoudi I, Wong SW. Viral interferon regulatory factors are critical for delay of the host immune response against rhesus macaque rhadinovirus infection. J Virol. 2012 Mar; 86(5): 2769-79. PMCID: PMC3302252
3: Wahl-Jensen V, Kurz S, Feldmann F, Buehler LK, Kindrachuk J, DeFilippis VR, da Silva Correia J, Früh K, Kuhn JH, Burton DR, Feldmann H. Ebola virion attachment and entry into human macrophages profoundly effects early cellular gene expression. PLoS Negl Trop Dis. 2011 Oct; 5(10):e1359. PMCID: PMC3196478
4: Botto S, Streblow DN, DeFilippis VR, White L, Kreklywich CN, Smith PP, Caposio P. IL-6 in human cytomegalovirus secretome promotes angiogenesis and survival of endothelial cells through the stimulation of survivin. Blood. 2011 Jan 6; 117(1): 352-61. PMCID: PMC3037756
5: White LK, Sali T, Alvarado D, Gatti E, Pierre P, Streblow D, Defilippis VR. Chikungunya virus induces IPS-1-dependent innate immune activation and protein kinase R-independent translational shutoff. J Virol. 2011 Jan; 85(1): 606-20. PMCID: PMC3014158
6: DeFilippis VR, Sali T, Alvarado D, White L, Bresnahan W, Früh KJ. Activation of the interferon response by human cytomegalovirus occurs via cytoplasmic double-stranded DNA but not glycoprotein B. J Virol. 2010 Sep; 84(17): 8913-25. PMCID: PMC2919031
7: Viswanathan K, Früh K, DeFilippis VR. Viral hijacking of the host ubiquitin system to evade interferon responses. Curr Opin Microbiol. 2010 Aug; 13(4): 517-23. Review. PMCID: PMC2939720
8: DeFilippis VR, Alvarado D, Sali T, Rothenburg S, Früh K. Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1. J Virol. 2010 Jan; 84(1): 585-98 PMCID: PMC2798427
9: Vomaske J, Melnychuk RM, Smith PP, Powell J, Hall L, DeFilippis VR, Früh K, Smit M, Schlaepfer DD, Nelson JA, Streblow DN. Differential ligand binding to a human cytomegalovirus chemokine receptor determines cell type-specific motility. PLoS Pathog. 2009 Feb; 5(2): e1000304 PMCID: PMC2637432
10: Medigeshi GR, Lancaster AM, Hirsch AJ, Briese T, Lipkin WI, Defilippis VR, Früh K, Mason PW, Nikolich-Zugich J, Nelson JA. West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis. J Virol. 2007 Oct; 81(20): 10849-60. PMCID: PMC2045561
11: Streblow DN, van Cleef KW, Kreklywich CN, Meyer C, Smith P, Defilippis VR, Grey F, Früh K, Searles R, Bruggeman C, Vink C, Nelson JA, Orloff SL. Rat cytomegalovirus gene expression in cardiac allograft recipients is tissue specific and does not parallel the profiles detected in vitro. J Virol. 2007 Apr; 81(8): 3816-26. PMCID: PMC1866122
12: DeFilippis VR. Induction and evasion of the type I interferon response by cytomegaloviruses. Adv Exp Med Biol. 2007; 598: 309-24. Review. PMID: 17892221
13: DeFilippis VR, Robinson B, Keck TM, Hansen SG, Nelson JA, Früh KJ. Interferon regulatory factor 3 is necessary for induction of antiviral genes during human cytomegalovirus infection. J Virol. 2006 Jan; 80(2): 1032-7. PMCID: PMC1346858
14: Hirsch AJ, Medigeshi GR, Meyers HL, DeFilippis VR, Früh K, Briese T, Lipkin WI, Nelson JA. The Src family kinase c-Yes is required for maturation of West Nile virus particles. J Virol. 2005 Sep; 79(18): 11943-51. PMCID: PMC1212629
15: DeFilippis VR, Früh K. Rhesus cytomegalovirus particles prevent activation of interferon regulatory factor 3. J Virol. 2005 May; 79(10): 6419-31. PMCID: PMC1091669
16: Rue CA, Jarvis MA, Knoche AJ, Meyers HL, DeFilippis VR, Hansen SG, Wagner M, Früh K, Anders DG, Wong SW, Barry PA, Nelson JA. A cyclooxygenase-2 homologue encoded by rhesus cytomegalovirus is a determinant for endothelial cell tropism. J Virol. 2004 Nov; 78(22): 12529-36. PMCID: PMC525102
17: McAllister SC, Hansen SG, Ruhl RA, Raggo CM, DeFilippis VR, Greenspan D, Früh K, Moses AV. Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells. Blood. 2004 May 1; 103(9): 3465-73. PMID: 14726403
18: DeFilippis VR, Raggo C, Moses A, Früh K. Functional genomics in virology and antiviral drug discovery. Trends Biotechnol. 2003 Oct; 21(10): 452-7. Review. PMID: 14512232
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