Frank Chisari, MD
Scripps Research Joint Appointments
Research Focus
Immunobiology and Pathogenesis of
Hepatitis B and C Virus Infection
The outcome of noncytolytic viral infections is largely determined by the cellular immune response. My laboratory focussed on the host-virus interactions that determine the outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Using a combination of real time viral dynamics, development of cell-based and animal models of HBV and HCV infection, and quantitative functional T cell analysis of infected humans and subhuman primates and in transgenic mice, we demonstrated a direct relationship between viral clearance and the vigor, kinetics and homing potential of the antiviral T cell response to HBV and HCV, the rate with which they spread after inoculation, their ability to escape immune recognition, and the host and viral mechanisms that determine viral clearance and persistence and the development of hepatocellular carcinoma. In the course of those studies we discovered that virus-specific T cells can suppress viral replication noncytolytically by secreting antiviral cytokines that can purge viruses from infected cells without killing them, i.e. a third effector limb in the immune response besides antibody neutralization and T cell-mediated destruction of infected cells. This led to studies that identified the intracellular antiviral effector pathways that are triggered by these cytokines, pinpointed the steps in the viral life cycles that are targeted by the cytokines, and defined the mechanisms deployed by the viruses to defeat their antiviral effects.
Education
M.D. (Medicine), Weill Cornell Medical College, 1968A.B. (Biology), Fordham University, 1963
M.D., New York Hospital / Cornell Medical Center, 1969
M.D., Pasteur Institute (Institut Pasteur), Molecular Biology: Fogarty International Scholar, Unite de Recombinaison et Expression Genetique, 1984
M.D., Mary Hitchcock Memorial Hospital, 1973
M.D., National Institutes of Health, 1972
M.D., Scripps Clinic and Research Foundation, 1975
M.D., Mayo Clinic, 1970
M.D., Cornell University Medical College, 1967
Professional Experience
2015-2017 Professor Emeritus, Immunology and Microbial Science (IMS), Scripps Research-2013 Professor, Immunology and Microbial Science (IMS), Scripps Research
Awards & Professional Activities
Awards NIH MERIT Award, 1990-2000; Member, Association of American Physicians, 1992; Fellow, American Association for the Advancement of Science, 1996; Ernst Jung Prize in Medicine,1997; Rous-Whipple Award, American Society for Investigative Pathology, 1999; Distinguished Advisory Committee, UCSD Cancer Center, 2000-; Review Panel, Int'l Research Scholars Program, Howard Hughes Med. Inst., 2000-; Scientific Advisory Board, Center for the Study of HCV, Rockefeller Univ., 2000-; Board of Scientific Councilors, NIAID, NIH, 2001 Blue Ribbon Panel on Bioterrorism Research, NIAID, NIH, 2002; Expert Panel on Immunity and Biodefense, NIAID, NIH, 2002; Fellow, American Academy of Microbiology, 2002; Member, National Academy of Sciences, 2002; Member, Institute of Medicine, National Academy of Sciences, 2003; Distinguished Alumnus Award, Weill-Cornell University Medical College, 2004; ISI Highly Cited Researcher, 2006-present; Distinguished Scientist Award, Hepatitis B Foundation, 2007; William H. Prusoff/HepDART Lifetime Achievement Award, 2015.
Review Committees and Advisory Boards
-Pathology B Study Section and Reviewers' Reserve, National Institutes of Health, 1988-92
-Scientific Review Board, German Cancer Research Center, Heidelberg, Germany, 1990-91
-Hepatitis Panel, US-Japan Cooperative Medical Science Program, 1992-1998
-Hepadnaviridae Study Group, International Committee and Taxonomy of Viruses, 1994-98
-Scientific Advisory Board, Liver Research Ctr., Albert Einstein Coll. of Medicine, 1995-01
-Nominating Committee, American Society for Investigative Pathology, 1999-2002
-Distinguished Advisory Committee, UCSD Cancer Center, 2000-2015
-Scientific Advisory Board, Center for Genetics and Genomics, Brown University, 2000-02
-Review Panel, Int'l Research Scholars Program, Howard Hughes Med. Inst., 2000
-Scientific Advisory Board, Center for the Study of HCV, Rockefeller Univ., 2000-2015
-Board of Scientific Councilors (ad hoc), NIAID, NIH, 2001, 2005
-Blue Ribbon Panel on Bioterrorism Research, NIAID, NIH, 2002
-Expert Panel on Immunity and Biodefense, NIAID, NIH, 2002
-Class IV Membership Committee, National Academy of Sciences, 2004, 2005, 2008, 2010
-Scientific Advisory Board, Northeast Biodefense Center, 2004-2015
-National Advisory Committee, The Pew Scholars Program in Biomedical Sciences, 2006-9
Editorial Boards
-American Journal of Pathology
-Hepatology
-Journal of Clinical Investigation
-Journal of Experimental Pathology
-Journal of Immunology
-Journal of Virology
-Microbial Pathogenesis
-PLoS Pathogens
-Viral Immunology
-Virology
-Current Opinion in Virology.
Professional Societies
-American Society for Virology
-American Association of Immunologists
-American Society for Investigative Pathology
-Amderican Association for the Study of Liver Disease
-American Association for Cancer Research
-American Association for the Advancement of Science
-Henry Kunkel Society
-Molecular Medicine Society.
Selected References
SELECTED PUBLICATIONS SINCE 2005
Longatti A, Boyd B, Chisari FV. Virion-Independent Transfer of Replication-Competent Hepatitis C Virus RNA between Permissive Cells. J Virol. 2015 Mar 1;89(5):2956-61. PMID:25505060
Chisari FV, Mason WS, Seeger C Comment on "Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA".Science. 2014 Jun 13;344(6189):1237. Science.1254082. PMID:24926010
Wieland SF, Asabe S, Engle RE, Purcell RH, Chisari FV. Limited HBV Replication Space in the Chronically HCV-infected Liver. J Virol. 2014 May;88(9):5184-8. PMID: 24522924
Wieland SF, Takahashi K, Boyd B, Whitten-Bauer C, Ngo N, de la Torre JC, Chisari FV. Human plasmacytoid dendritic cells sense lymphocytic choriomeningitis virus-infected cells in vitro. J Virol. 2014 Jan;88(1):752-7. PMID: 2415539
Wieland S, Makowska Z, Campana B, Calabrese D, Dill MT, Chung J, Chisari FV, Heim MH. Simultaneous detection of hepatitis C virus and interferon stimulated gene expression in infected human liver. Hepatology. 2014 Jun;59(6):2121-30 PMID: 24122862
Isogawa M, Chung J, Murata Y, Kakimi K, Chisari FV CD40 activation rescues antiviral CD8? T cells from PD-1-mediated exhaustion. PLoS Pathog. 2013;9(7):e1003490. doi: 10.1371/journal.ppat.1003490. PMID: 23853599 Free PMC Article
Dreux M, Garaigorta U, Boyd B, Décembre E, Chung J, Whitten-Bauer C, Wieland S, Chisari FV. Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. Cell Host Microbe. 2012 Oct 18;12(4):558-70. PMID: 23084922
Garaigorta U, Heim MH, Boyd B, Wieland S, Chisari FV. Hepatitis C virus (HCV) induces formation of stress granules whose proteins regulate HCV RNA replication and virus assembly and egress. J Virol. 2012 Oct;86(20):11043-56. PMID: 22855484
Sitia G, Aiolfi R, Di Lucia P, Mainetti M, Fiocchi A, Mingozzi F, Esposito A, Ruggeri ZM, Chisari FV, Iannacone M, Guidotti LG. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):E2165-72. PMID: 22753481
Montero A, Gastaminza P, Law M, Cheng G, Chisari FV, Ghadiri MR. Self-assembling peptide nanotubes with antiviral activity against hepatitis C virus. Chem Biol. 2011 Nov 23;18(11):1453-62. PMID: 22118679
Chisari FV, García-Sastre A. Pioneers of pathogenesis: past and present. Curr Opin Virol. 2011 Sep;1(3):157-9. PMID: 22440715.
Dreux M, Chisari FV. Impact of the autophagy machinery on hepatitis C virus infection. Viruses. 2011 Aug;3(8):1342-57. Review. PMID: 21994783; Free full text
Sitia G, Iannacone M, Aiolfi R, Isogawa M, van Rooijen N, Scozzesi C, Bianchi ME, von Andrian UH, Chisari FV, Guidotti LG. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. PLoS Pathog. 2011 Jun;7(6):e1002061. doi: 10.1371/journal.ppat.1002061. PMID: 21655107. Free full text Cited in PMC
Gastaminza P, Pitram SM, Dreux M, Krasnova LB, Whitten-Bauer C, Dong J, Chung J, Fokin VV, Sharpless KB, Chisari FV. Antiviral stilbene 1,2-diamines prevent initiation of hepatitis C virus RNA replication at the outset of infection. J Virol. 2011 Jun;85(11):5513-23. PMID: 21430055. Free full text
MacPherson JI, Sidders B, Wieland S, Zhong J, Targett-Adams P, Lohmann V, Backes P, Delpuech-Adams O, Chisari F, Lewis M, Parkinson T, Robertson DL. An integrated transcriptomic and meta-analysis of hepatoma cells reveals factors that influence susceptibility to HCV infection. PLoS One. 2011;6(10):e25584. PMID: 22046242. Free full text
Gastaminza P, Dryden KA, Boyd B, Wood MR, Law M, Yeager M, Chisari FV. Ultrastructural and biophysical characterization of hepatitis C virus particles produced in cell culture. J Virol. 2010 Nov;84(21):10999-1009. PMID: 20686033. Free full text Cited in PMC
Chisari FV, Isogawa M, Wieland SF. Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris). 2010 Aug;58(4):258-66. Epub 2010 Feb 8. Review. PMID: 20116937. Free full text Cited in PMC
Chatterji U, Lim P, Bobardt MD, Wieland S, Cordek DG, Vuagniaux G, Chisari F, Cameron CE, Targett-Adams P, Parkinson T, Gallay PA. HCV resistance to cyclosporin A does not correlate with a resistance of the NS5A-cyclophilin A interaction to cyclophilin inhibitors. J Hepatol. 2010 Jul;53(1):50-6. PMID: 20451281. Free full text Cited in PMC
Takahashi K, Asabe S, Wieland S, Garaigorta U, Gastaminza P, Isogawa M, Chisari FV. Plasmacytoid dendritic cells sense hepatitis C virus-infected cells, produce interferon, and inhibit infection. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7431-6. PMID: 20231459. Free full text Cited in PMC
Dreux M, Chisari FV. Viruses and the autophagy machinery. Cell Cycle. 2010 Apr 1;9(7):1295-1307. Review. PubMed PMID: 20305376. Cited in PMC
Bissig KD, Wieland SF, Tran P, Isogawa M, Le TT, Chisari FV, Verma IM. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J Clin Invest. 2010 Mar;120(3):924-30. PMID: 20179355. Free full text Cited in PMC
Bandi P, Garcia ML, Booth CJ, Chisari FV, Robek MD. Bortezomib inhibits hepatitis B virus replication in transgenic mice. Antimicrob Agents Chemother. 2010 Feb;54(2):749-56. PMID: 19949053. Free full text Cited in PMC
Yang PL, Althage A, Chung J, Maier H, Wieland S, Isogawa M, Chisari FV. Immune effectors required for hepatitis B virus clearance. Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):798-802. PMID: 20080755. Free full text Cited in PMC
Gastaminza P, Whitten-Bauer C, Chisari FV. Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):291-6. PMID: 19995961. Free full text Cited in PMC
Garaigorta U, Chisari FV. Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation. Cell Host Microbe. 2009 Dec 17;6(6):513-22. PMID: 20006840. Free full text Cited in PMC
Dreux M, Chisari FV. Autophagy proteins promote hepatitis C virus replication. Autophagy. 2009 Nov;5(8):1224-5. PMID: 19844160. Cited in PMC
Asabe S, Wieland SF, Chattopadhyay PK, Roederer M, Engle RE, Purcell RH, Chisari FV. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol. 2009 Oct;83(19):9652-62. PMID: 19625407. Free full text Cited in PMC
Dreux M, Gastaminza P, Wieland SF, Chisari FV. The autophagy machinery is required to initiate hepatitis C virus replication. Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14046-51. PMID: 19666601. Free full text Cited in PMC
Bukh J, Thimme R, Meunier JC, Faulk K, Spangenberg HC, Chang KM, Satterfield W, Chisari FV, Purcell RH. Previously infected chimpanzees are not consistently protected against reinfection or persistent infection after reexposure to the identical hepatitis C virus strain. J Virol. 2008 Aug;82(16):8183-95. PMID: 18550671. Free full text Cited in PMC
Bobardt MD, Cheng G, de Witte L, Selvarajah S, Chatterji U, Sanders-Beer BE, Geijtenbeek TB, Chisari FV, Gallay PA. Hepatitis C virus NS5A anchor peptide disrupts human immunodeficiency virus. Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5525-30. PMID: 18378908. Free full text Cited in PMC
Gastaminza P, Cheng G, Wieland S, Zhong J, Liao W, Chisari FV. Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion. J Virol. 2008 Mar;82(5):2120-9. PMID: 18077707. Free full text Cited in PMC
Cheng G, Montero A, Gastaminza P, Whitten-Bauer C, Wieland SF, Isogawa M, Fredericksen B, Selvarajah S, Gallay PA, Ghadiri MR, Chisari FV. A virocidal amphipathic {alpha}-helical peptide that inhibits hepatitis C virus infection in vitro. Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3088-93. PMID: 18287023. Free full text Cited in PMC
Iannacone M, Sitia G, Isogawa M, Whitmire JK, Marchese P, Chisari FV, Ruggeri ZM, Guidotti LG. Platelets prevent IFN-alpha/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):629-34. PMID: 18184798. Free full text Cited in PMC
Law M, Maruyama T, Lewis J, Giang E, Tarr AW, Stamataki Z, Gastaminza P, Chisari FV, Jones IM, Fox RI, Ball JK, McKeating JA, Kneteman NM, Burton DR. Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat Med. 2008 Jan;14(1):25-7. PMID: 18064037. Cited in PMC
Pedersen IM, Cheng G, Wieland S, Volinia S, Croce CM, Chisari FV, David M. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature. 2007 Oct 18;449(7164):919-22. PMID: 17943132. Free full text Cited in PMC
Sidney J, Peters B, Moore C, Pencille TJ, Ngo S, Masterman KA, Asabe S, Pinilla C, Chisari FV, Sette A. Characterization of the peptide-binding specificity of the chimpanzee class I alleles A 0301 and A 0401 using a combinatorial peptide library. Immunogenetics. 2007 Sep;59(9):745-51. PMID: 17701407. Cited in PMC
Sakai A, Takikawa S, Thimme R, Meunier JC, Spangenberg HC, Govindarajan S, Farci P, Emerson SU, Chisari FV, Purcell RH, Bukh J. In vivo study of the HC-TN strain of hepatitis C virus recovered from a patient with fulminant hepatitis: RNA transcripts of a molecular clone (pHC-TN) are infectious in chimpanzees but not in Huh7.5 cells. J Virol. 2007 Jul;81(13):7208-19. PMID: 17409145. Free full text Cited in PMC
Cheng G, Zhong J, Chung J, Chisari FV. Double-stranded DNA and double-stranded RNA induce a common antiviral signaling pathway in human cells. Proc Natl Acad Sci U S A. 2007 May 22;104(21):9035-40. PMID: 17517627. Free full text Cited in PMC
Maier H, Isogawa M, Freeman GJ, Chisari FV. PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver. J Immunol. 2007 Mar 1;178(5):2714-20. PubMed PMID: 17312113. Cited in PMC
Robek MD, Garcia ML, Boyd BS, Chisari FV. Role of immunoproteasome catalytic subunits in the immune response to hepatitis B virus. J Virol. 2007 Jan;81(2):483-91. PMID: 17079320. Free full text Cited in PMC
Kapadia SB, Barth H, Baumert T, McKeating JA, Chisari FV. Initiation of hepatitis C virus infection is dependent on cholesterol and cooperativity between CD81 and scavenger receptor B type I. J Virol. 2007 Jan;81(1):374-83. PMID: 17050612. Free full text Cited in PMC
Gastaminza P, Kapadia SB, Chisari FV. Differential biophysical properties of infectious intracellular and secreted hepatitis C virus particles. J Virol. 2006 Nov;80(22):11074-81. PMID: 16956946. Free full text Cited in PMC
Zhong J, Gastaminza P, Chung J, Stamataki Z, Isogawa M, Cheng G, McKeating JA, Chisari FV. Persistent hepatitis C virus infection in vitro: coevolution of virus and host. J Virol. 2006 Nov;80(22):11082-93. PMID: 16956932. Free full text Cited in PMC
Uprichard SL, Chung J, Chisari FV, Wakita T. Replication of a hepatitis C virus replicon clone in mouse cells. Virol J. 2006 Oct 28;3:89. PubMed PMID: 17069661. Free full text Cited in PMC
Sainz B Jr, Chisari FV. Production of infectious hepatitis C virus by well-differentiated, growth-arrested human hepatoma-derived cells. J Virol. 2006 Oct;80(20):10253-7. PubMed PMID: 17005703. Free full text Cited in PMC
Sidney J, Asabe S, Peters B, Purton KA, Chung J, Pencille TJ, Purcell R, Walker CM, Chisari FV, Sette A. Detailed characterization of the peptide binding specificity of five common Patr class I MHC molecules. Immunogenetics. 2006 Jul;58(7):559-70. PMID: 16791621. Cited in PMC
Dryden KA, Wieland SF, Whitten-Bauer C, Gerin JL, Chisari FV, Yeager M. Native hepatitis B virions and capsids visualized by electron cryomicroscopy. Mol Cell. 2006 Jun 23;22(6):843-50. PubMed PMID: 16793552. Cited in PMC
Cheng G, Zhong J, Chisari FV. Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms. Proc Natl Acad Sci U S A. 2006 May 30;103(22):8499-504. PMID: 16707574. Free full text Cited in PMC
Kimura K, Moriwaki H, Nagaki M, Saio M, Nakamoto Y, Naito M, Kuwata K, Chisari FV. Pathogenic role of B cells in anti-CD40-induced necroinflammatory liver disease. Am J Pathol. 2006 Mar;168(3):786-95. PubMed PMID: 16507894. Free full text Cited in PMC
Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol. 2006;1:23-61. Review. PMID: 18039107. Cited in PMC
Murray JM, Wieland SF, Purcell RH, Chisari FV. Dynamics of hepatitis B virus clearance in chimpanzees. Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17780-5. PMID: 16306261. Free full text Cited in PMC
Iannacone M, Sitia G, Isogawa M, Marchese P, Castro MG, Lowenstein PR, Chisari FV, Ruggeri ZM, Guidotti LG. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med. 2005 Nov;11(11):1167-9. PMID: 16258538. Free full text Cited in PMC
Gilbert RJ, Beales L, Blond D, Simon MN, Lin BY, Chisari FV, Stuart DI, Rowlands DJ. Hepatitis B small surface antigen particles are octahedral. Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14783-8. PMID: 16203986. Free full text Cited in PMC
Chisari FV. Unscrambling hepatitis C virus-host interactions. Nature. 2005 Aug 18;436(7053):930-2. PubMed PMID: 16107831. Cited in PMC
Wieland SF, Chisari FV. Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol. 2005 Aug;79(15):9369-80. Review. PMID: 16014900. Free full text Cited in PMC
Wieland SF, Eustaquio A, Whitten-Bauer C, Boyd B, Chisari FV. Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids. Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9913-7. PMID: 15994231. Free full text Cited in PMC
Isogawa M, Furuichi Y, Chisari FV. Oscillating CD8(+) T cell effector functions after antigen recognition in the liver. Immunity. 2005 Jul;23(1):53-63. PubMed PMID: 16039579. Cited in PMC
Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T, Burton DR, Wieland SF, Uprichard SL, Wakita T, Chisari FV. Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9294-9. PMID: 15939869. Free full text Cited in PMC
Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol. 2005 Jun;79(11):7269-72. PMID: 15890966. Free full text Cited in PMC
Bui HH, Sidney J, Peters B, Sathiamurthy M, Sinichi A, Purton KA, Mothé BR, Chisari FV, Watkins DI, Sette A. Automated generation and evaluation of specific MHC binding predictive tools: ARB matrix applications. Immunogenetics. 2005 Jun;57(5):304-14. PMID: 15868141. Cited in PMC
Isogawa M, Kakimi K, Kamamoto H, Protzer U, Chisari FV. Differential dynamics of the peripheral and intrahepatic cytotoxic T lymphocyte response to hepatitis B surface antigen. Virology. 2005 Mar 15;333(2):293-300. PubMed PMID: 15721363. Cited in PMC
Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication. J Virol. 2005 Mar;79(6):3851-4. PubMed PMID: 15731279. Free full text Cited in PMC
Chen M, Sällberg M, Hughes J, Jones J, Guidotti LG, Chisari FV, Billaud JN, Milich DR. Immune tolerance split between hepatitis B virus precore and core proteins. J Virol. 2005 Mar;79(5):3016-27. PMID: 15709022. Free full text Cited in PMC
Kapadia SB, Chisari FV. Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2561-6. PMID: 15699349. Free full text Cited in PMC
Neumann-Haefelin C, Blum HE, Chisari FV, Thimme R. T cell response in hepatitis C virus infection. J Clin Virol. 2005 Feb;32(2):75-85. Review. PMID: 15653409. Cited in PMC
