The Hirsch lab studies multiple facets of the interaction of flaviviruses with the infected host. Currently, our work focuses on Zika, West Nile, and dengue viruses, although we can extend our research to newly emerging pathogens. We are interested in identifying and characterizing important cellular proteins/ pathways involved in flaviviruses infection, as well as the interplay between the virus and cellular innate immunity. This work has also been extended to translational programs directed at the discovery of anti-flaviviral molecules, and the identification of adjuvants that boost the response to flavivirus specific vaccine candidates. The lab is also interested in flavivirus pathogenesis, and to this end we have established a non-human primate model of Zika virus infection, allowing investigation of mechanisms of fetal injury during viral infection and testing of potential therapeutic interventions.  

Biography

Alec Hirsch graduated from Swathmore College in Pennsylvania with a B.A. in Biology in 1989 and received his Ph.D. in molecular Biology from Princeton University in 1999. He came to OHSU on a postdoctoral fellowship with Dr. Jay Nelson as his advisor. He was hired as Assistant Scientist at OHSU Vaccine and Gene Therapy Institute in 2010.

Publications

• Dudley DM, Van Rompay KK, Coffey LL, Ardeshir A, Keesler RI, Bliss-Moreau E, et al. Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates. Nat Med. 2018 Aug;24(8):1104–7. PMCID: PMC6082723
• Smith JL, Sheridan K, Parkins CJ, Frueh L, Jemison AL, Strode K, et al. Characterization and structure-activity relationship analysis of a class of antiviral compounds that directly bind dengue virus capsid protein and are incorporated into virions. Antiviral Res. 2018 Jul;155:12–9.
• Hirsch AJ, Roberts VHJ, Grigsby PL, Haese N, Schabel MC, Wang X, et al. Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology. Nat Comms. 2018 Jan 17;9(1):263. PMCID: PMC5772047
• Pryke KM, Abraham J, Sali TM, Gall BJ, Archer I, Liu A, et al. A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses. Dermody TS, editor. mBio. American Society for Microbiology; 2017 May 2;8(3):243–22. PMCID: PMC5414005
• Smith JL, Jeng S, McWeeney SK, Hirsch AJ. A MicroRNA Screen Identifies the Wnt Signaling Pathway as a Regulator of the Interferon Response during Flavivirus Infection. J Virol. 2017 Apr 15;91(8):e02388–16. PMCID: PMC5375670
• Hirsch AJ, Smith JL, Haese NN, Broeckel RM, Parkins CJ, Kreklywich C, et al. Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues. Geisbert T, editor. PLoS Pathog. 2017 Mar;13(3):e1006219. PMCID: PMC5344528
• Hirsch AJ. Modeling Zika virus infection in nonhuman primates. Future Virology. 2017;12(9):479–83.
• Smith JL, Stein DA, Shum D, Fischer MA, Radu C, Bhinder B, et al. Inhibition of dengue virus replication by a class of small-molecule compounds that antagonize dopamine receptor d4 and downstream mitogen-activated protein kinase signaling. J Virol. 2014 May;88(10):5533–42. PMCID: PMC4019099
• Fischer MA, Smith JL, Shum D, Stein DA, Parkins C, Bhinder B, et al. Flaviviruses Are Sensitive to Inhibition of Thymidine Synthesis Pathways. J Virol. 2013 Aug 13;87(17):9411–9.
• Smith JL, Grey FE, Uhrlaub JL, Nikolich-Zugich J, Hirsch AJ. Induction of the cellular microRNA, Hs_154, by West Nile virus contributes to virus-mediated apoptosis through repression of antiapoptotic factors. J Virol. 2012 May;86(9):5278–87. PMCID: PMC3347395
• Stein DA, Perry ST, Buck MD, Oehmen CS, Fischer MA, Poore E, et al. Inhibition of Dengue Virus Infections in Cell Cultures and in AG129 Mice by a Small Interfering RNA Targeting a Highly Conserved Sequence. J Virol. 2011 Oct;85(19):10154–66. PMCID: PMC3196423
• Shum D, Smith JL, Hirsch AJ, Bhinder B, Radu C, Stein DA, et al. High-content assay to identify inhibitors of dengue virus infection. Assay Drug Dev Technol. 2010 Oct;8(5):553–70. PMCID: PMC2962577
• Hirsch AJ. The use of RNAi-based screens to identify host proteins involved in viral replication. Future Microbiol. 2010 Feb;5(2):303–11.
• Wertheimer AM, Uhrlaub JL, Hirsch A, Medigeshi G, Sprague J, Legasse A, et al. Immune response to the West Nile virus in aged non-human primates. PLoS ONE. 2010;5(12):e15514. PMCID: PMC2996299
• Brien JD, Uhrlaub JL, Hirsch A, Wiley CA, Nikolich-Zugich J. Key role of T cell defects in age-related vulnerability to West Nile virus. J. Exp. Med. 2009 Nov 23;206(12):2735–45. PMCID: PMC2806630
• Medigeshi GR, Hirsch AJ, Brien JD, Uhrlaub JL, Mason PW, Wiley C, et al. West nile virus capsid degradation of claudin proteins disrupts epithelial barrier function. J Virol. 2009 Jun;83(12):6125–34. PMCID: PMC2687390
• Medigeshi GR, Hirsch AJ, Streblow DN, Nikolich-Zugich J, Nelson JA. West Nile virus entry requires cholesterol-rich membrane microdomains and is independent of alphavbeta3 integrin. J Virol. American Society for Microbiology Journals; 2008 Jun;82(11):5212–9. PMCID: PMC2395215
• Medigeshi GR, Lancaster AM, Hirsch AJ, Briese T, Lipkin WI, Defilippis V, et al. 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
• Barklis E, Still A, Sabri MI, Hirsch AJ, Nikolich-Zugich J, Brien J, et al. Sultam thiourea inhibition of West Nile virus. Antimicrob. Agents Chemother. 2007 Jul;51(7):2642–5. PMCID: PMC1913232
• Hirsch AJ, Medigeshi GR, Meyers HL, Defilippis V, Früh K, Briese T, et al. 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