Victor DeFilippis, Ph.D.

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.

Biography
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.

Selected Publications

L. White, T. Sali, D. Alvarado, E. Gatti, P. Pierre, D. Streblow, and V.R. DeFilippis. 2010. Chikungunya Virus Induces IPS-1-Dependent Innate Immune Activation and PKR-Independent Translational Shutoff. J. Virology (Epub 10/2010).

DeFilippis, V.R., T. Sali, D. Alvarado, L. White, W. Bresnahan, and K. Früh. 2010. Activation of the Interferon Response by Human Cytomegalovirus Occurs Via Cytoplasmic dsDNA but not Glycoprotein B. J. Virology 84: 8913-8925.

DeFilippis, V.R., D. Alvarado, T. Sali, S. Rothenburg, and K. Früh. 2010. Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1. J. Virology 84: 585-598.

DeFilippis, V.R. 2007. Induction and evasion of type I interferon responses by cytomegaloviruses. Adv Exp Med Biol 598: 309-24.

DeFilippis, V.R., B. Robinson, T. Keck, S.G. Hansen, J.A. Nelson and K.J. Früh. 2006. Interferon regulatory factor 3 is necessary for induction of antiviral genes during human cytomegalovirus infection. J. Virology 80: 1032-1037.

DeFilippis, V.R. and K.J. Früh. 2005. Inhibition of interferon regulatory factor 3 activation by rhesus cytomegalovirus virions. J. Virology 79:6419–6431.

DeFilippis, V.R., F.J. Ayala, and L.P. Villarreal. 2002. Evidence for diversifying selection in human papillomavirus type 16 E6 but not E7 oncogenes. J. Molecular Evolution 55:491-9.

DeFilippis, V.R. and L.P. Villarreal. 2001. Virus evolution. Chapter 13 in Fields Virology, edited by D.M. Knipe and P.M. Howley. Lippincott - Raven Publishers. Philadelphia.

Villarreal, L.P. and V.R. DeFilippis. 2000. A hypothesis for DNA viruses as the origin of eukaryotic replication proteins. J. Virology 74:7079-7084.