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Scripps Research Joint Appointments

Professor, Department of Immunology and Microbial Science

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. Our laboratory focusses 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 and quantitative functional T cell analysis, we have 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 and their ability to escape immune recognition. In addition, we have shown that there is a third effector limb in the immune response besides antibody neutralization and T cell-mediated destruction of infected cells: i.e. T cells also secrete antiviral cytokines that can purge viruses from infected cells without killing them. Currently we are applying genome-wide expression profiling to define the intracellular antiviral effector pathways that are triggered by these cytokines; biochemical, biophysical and molecular approaches to identify the points in the life cycles of these viruses that are targeted by these antiviral cytokines; and molecular immunological strategies to determine the mechanisms deployed by the viruses to defeat their antiviral effects.

Education

M.D., Medicine, Weill Cornell Medical College, New York, New York, 1968
A.B., Biology, Fordham University, New York, New York, 1963

Professional Experience

Training -
Anatomic Pathology: Fellow, Cornell University Medical College, New York 1966-1967; Fellow, Mayo Clinic, Rochester, Minnesota 1969-1970.
Internal Medicine: Intern, The New York Hospital-Cornell University Medical Center,New York, New York 1968-1969. Resident, Mary Hitchcock Memorial Hospital, Dartmouth Medical School, Hanover, New Hampshire 1972-1973.
Immunopathology: Staff Associate, Laboratory of Pathology, National Institutes of Health, Bethesda, Maryland 1970-72 Research Fellow, Department of Experimental Pathology, Scripps Clinic and Research Foundation, La Jolla, California  1973-1975.
Molecular Biology: Fogarty Scholar, Unite de Recombinaison et Expression Genetique, Institut Pasteur, Paris, France  1983-1984.
Employment -
1975-1981:  Assistant Professor, Departments of Molecular Immunology and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, California
1981 - 1988: Associate Professor, Department of Basic and Clinical Research, Research Institute of Scripps Clinic, La Jolla, California
1989-2004: Director, General Clinical Research Center, The Scripps Research Institute, La Jolla, California
1988-2008: Professor and Head, Division of Experimental Pathology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California
2008-Present: Professor and Head, Laboratory of Experimental Virology, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California

Awards & Professional Activities

NIH MERIT Award, 1990-2000, Member, Association of American Physicians, 1992, Fellow, American Association for the Advancement of Science, 1996-present, Ernst Jung Prize in Medicine ,1997, Rous-Whipple Award, American Society for Investigative Pathology, 1999, Distinguished Advisory Committee, UCSD Cancer Center, 2000-present Review Panel, Int'l Research Scholars Program, Howard Hughes Med. Inst., 2000-present Scientific Advisory Board, Center for the Study of HCV, Rockefeller Univ., 2000-present 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.

Selected References

                          SELECTED PUBLICATIONS SINCE 2005

1: 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. Epub 2010 Aug 4.
PubMed PMID: 20686033; PubMed Central PMCID: PMC2953183.

2: 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. Epub 2010 Mar 15. PubMed PMID: 20231459; PubMed Central PMCID:
PMC2867703.

3: 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 1;120(3):924-30. doi: 10.1172/JCI40094. Epub
2010 Feb 22. PubMed PMID: 20179355; PubMed Central PMCID: PMC2827952.

4: 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. Epub 2009 Dec 22. PubMed PMID: 20080755; PubMed
Central PMCID: PMC2818933.

5: 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. PubMed PMID: 20006840; PubMed Central PMCID: PMC2905238.

6: 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. Epub 2009 Jul 22.
PubMed PMID: 19625407; PubMed Central PMCID: PMC2748002.

7: 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. Epub 2009 Aug 3. PubMed PMID: 19666601; PubMed
Central PMCID: PMC2729017.

8: 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. Epub 2007 Dec 12. PubMed PMID:
18077707; PubMed Central PMCID: PMC2258938.

9: 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. Epub 2007 Dec 6. PubMed PMID: 18064037.

10: 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. PubMed PMID: 17943132; PubMed Central PMCID:
PMC2748825.

11: 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. Epub 2007 May 15. PubMed
PMID: 17517627; PubMed Central PMCID: PMC1885623.

12: 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. Epub 2006
Oct 18. PubMed PMID: 17050612; PubMed Central PMCID: PMC1797271.

13: 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. Epub 2006 Sep 6. PubMed PMID: 16956946; PubMed Central
PMCID: PMC1642172.

14: 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. Epub 2006 Sep 6. PubMed PMID:
16956932; PubMed Central PMCID: PMC1642175.

15: 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; PubMed Central PMCID: PMC1635043.

16: 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; PubMed Central PMCID: PMC1617281.

17: 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.

18: 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. Epub 2006 May
17. PubMed PMID: 16707574; PubMed Central PMCID: PMC1482521.

19: Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis.
Annu Rev Pathol. 2006;1:23-61. Review. PubMed PMID: 18039107.

20: Chisari FV. Unscrambling hepatitis C virus-host interactions. Nature. 2005
Aug 18;436(7053):930-2. PubMed PMID: 16107831.

21: Wieland SF, Chisari FV. Stealth and cunning: hepatitis B and hepatitis C
viruses. J Virol. 2005 Aug;79(15):9369-80. Review. PubMed PMID: 16014900; PubMed
Central PMCID: PMC1181548.

22: 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. Epub 2005
Jul 1. PubMed PMID: 15994231; PubMed Central PMCID: PMC1175012.

23: 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.

24: 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. Epub 2005 Jun 6. PubMed
PMID: 15939869; PubMed Central PMCID: PMC1166622.

25: 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.
PubMed PMID: 15890966; PubMed Central PMCID: PMC1112123.

26: 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; PubMed
Central PMCID: PMC1075734.

27: 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. Epub 2005 Feb 7. PubMed PMID: 15699349; PubMed Central PMCID:
PMC549027.

28: Uprichard SL, Boyd B, Althage A, Chisari FV. Clearance of hepatitis B virus
from the liver of transgenic mice by short hairpin RNAs. Proc Natl Acad Sci U S
A. 2005 Jan 18;102(3):773-8. Epub 2005 Jan 7. PubMed PMID: 15640346; PubMed
Central PMCID: PMC545555.

 

Links

Chisari bibliography

Chisari patents