OHSU

Victor R. DeFilippis

Research in Dr. DeFilippis’ laboratory focuses on the molecular biology of virus-host interactions especially with regard to the innate immune response to infection, its relation to pathogenesis, and the mechanisms employed by viruses to counteract, tolerate, or circumvent these reactions. He is particularly interested in the innate signaling receptors and associated pathways triggered during virus-cell contact that lead to synthesis of interferon and pro-inflammatory cytokines. His 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 immune response 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. Infection of human cells with HCMV triggers multiple innate immune responses that include secretion of type I interferon and pro-inflammatory cytokines. In contrast, the closely related cytomegalovirus of Rhesus macaques triggers no innate response following infection of Rhesus host cells. We are focused on identifying the cellular sensors and pathways triggered by cytomegalovirus infection, the viral components that stimulate this activation, and on characterizing the molecular basis of inhibition of this response by both Rhesus and human cytomegaloviruses. This work involves microarray and quantitative PCR based analysis of virus-induced gene expression, RNA interference-mediated gene expression knockdown, retrovirus-dependent stable cell line construction, and promoter activation analysis using reporter cells.

2) 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 undergone an explosive reemergence due to the arising of a new strain capable of being transmitted via a more widespread and 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 states 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. Ultimately this work aims to develop therapeutic techniques directed at alleviating CHIKV-induced arthritis through the inhibition of virus-triggered pro-inflammatory responses.

3) Discovery and characterization of novel antiviral compounds
Type I interferons have evolved in mammalian species to act as an antiviral immunological system that is effective against a broad spectrum of virus species. Using in vitro high throughput screens we have identified numerous novel small molecules capable of stimulating expression and secretion of interferon. Many of these compounds are capable of blocking replication of diverse RNA and DNA virus species. We are currently exploring the safety and efficacy of these molecules for antiviral use in animals as well as characterizing the cellular pathways through which they are operational.

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, OHSU.

Key References

White, L., T. Sali, D. Alvarado, E. Gatti, P. Pierre, D. Streblow, and V.R. DeFilippis. 2011. Chikungunya virus evades IPS-1-dependent induction of innate immunity by a PKR-independent translational shutoff mechanism. J. Virol. 85:606-620.

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. Virol. 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. Virol. 84:585-598.

Viswanathan, K., K. Früh, and V.R. DeFilippis. 2010. Viral hijacking of the host ubiquitin system to evade interferon responses. Curr. Opin. Microbiol. 13:1-7.

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. Virol. 80:1032-1037.

DeFilippis, V.R. and K.J. Früh. 2005. Inhibition of interferon regulatory factor 3 activation by rhesus cytomegalovirus virions. J. Virol. 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. Mol. Evol. 55:491-499.

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.