Dr. Jaisri R. Lingappa |
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University of Washington School of Public Health and Community Medicine Pathobiology Associate ProfessorAppointed: 2005 University of Washington School of Medicine Medicine Allergy and Infectious Disease Adjunct Associate ProfessorAppointed: 2005 |  |
Mailing AddressDepartment of Pathobiology School of Public Health Box 357238, Heatlh Science Building, Room F-155 University of Washington Seattle, Washington 98195-3873United States | Contact Information |
Qualifications
M.D., University of Massachusetts Medical School (Worcester), 1987.
Ph.D., Harvard University, Cell Biology, 1985.
B.A., Swarthmore College, Biology, 1979.
Expertise and Research Interests
The Lingappa laboratory uses a cell biological approach to study the assembly of viral capsids which are the protein shells that enclose and protect viral genomes. Capsid assembly occurs late in the viral life cycle and is necessary for production of infectious virions. Viruses must negotiate the mammalian cytoplasm with its numerous host defenses in order to assemble the vast number of viruses that are needed to spread the viral infection. In the past few years, work by our group and others has revealed that, contrary to expectations, capsid assembly is an ordered and highly regulated process. Furthermore, some viruses have evolved the ability to use proteins present in the host to promote efficient virus assembly.
My lab is interested in identifying cellular factors that are critical for viral capsid formation, and understanding their mechanisms of action. Our experimental approach involves studying the process of capsid assembly in cell extracts and in intact mammalian cells. Our "cell-free systems" use cell extracts to faithfully reconstitute capsid formation. Events that occur extremely rapidly in cells are less efficient in cell-free systems, allowing them to be identified, manipulated, and dissected. After using our cell-free systems to identifying viral-host interactions, we then use intact cells to verify our findings. To date, we have established cell-free systems for the assembly of human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 1 (HIV-2), simian immunodeficiency virus (SIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) capsids.
In the case of HIV-1, we demonstrated that assembly occurs via multi-step, energy-dependent pathway involving assembly intermediates and requiring host factors. We showed that a cellular protein termed HP68 (also called RNase L inhibitor or ABC protein E) associates with the assembling capsid protein, Gag, in the cell-free system as well as in HIV-1 infected T cells. HP68 appears to play an essential role in post-translational events of immature HIV-1 capsid assembly. HP68 also associates with additional HIV-1 proteins that are critical for assembly of infectious virions, namely HIV-1 Gag-Pol and Vif. HP68 is an unusual ATP-binding protein whose function in normal cells is poorly understood, but is likely to promote conformational changes.
For more information, see our lab's website at http://faculty.washington.edu/jais/
My lab is interested in identifying cellular factors that are critical for viral capsid formation, and understanding their mechanisms of action. Our experimental approach involves studying the process of capsid assembly in cell extracts and in intact mammalian cells. Our "cell-free systems" use cell extracts to faithfully reconstitute capsid formation. Events that occur extremely rapidly in cells are less efficient in cell-free systems, allowing them to be identified, manipulated, and dissected. After using our cell-free systems to identifying viral-host interactions, we then use intact cells to verify our findings. To date, we have established cell-free systems for the assembly of human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 1 (HIV-2), simian immunodeficiency virus (SIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) capsids.
In the case of HIV-1, we demonstrated that assembly occurs via multi-step, energy-dependent pathway involving assembly intermediates and requiring host factors. We showed that a cellular protein termed HP68 (also called RNase L inhibitor or ABC protein E) associates with the assembling capsid protein, Gag, in the cell-free system as well as in HIV-1 infected T cells. HP68 appears to play an essential role in post-translational events of immature HIV-1 capsid assembly. HP68 also associates with additional HIV-1 proteins that are critical for assembly of infectious virions, namely HIV-1 Gag-Pol and Vif. HP68 is an unusual ATP-binding protein whose function in normal cells is poorly understood, but is likely to promote conformational changes.
For more information, see our lab's website at http://faculty.washington.edu/jais/
Other Expertise
Medical License, California; 1988 to present
Certified in Internal Medicine, American Board of Internal Medicine; 1990-2000
Certified in Infectious Disease, American Board of Internal Medicine; 1992-2002
Certified in Internal Medicine, American Board of Internal Medicine; 1990-2000
Certified in Infectious Disease, American Board of Internal Medicine; 1992-2002
Future Research
Current and future projects in my lab include:
1. Identifying how the cellular factor HP68 uses energy to promote HIV-1 capsid assembly
2. Examining whether highly pathogenic HIV-1 variants utilize HP68 more effectively thereby leading to increased virion production
3. Identifying other viral-host interactions important for HIV-1 capsid formation
4. Determining whether human HP68 polymorphisms influence susceptibility to HIV-1 infection or progression to AIDS
5. Understanding how HCV encapsidates its genome and why assembly of this virus is blocked in cultured cell lines
6. Establishing novel cell-free systems to study assembly of other viruses that cause diseases relevant to public health
7. Understanding the enzymatic activity and function of endogenously expressed proteins in the APOBEC family, which includes cytidine deaminases that act as restriction factors.
1. Identifying how the cellular factor HP68 uses energy to promote HIV-1 capsid assembly
2. Examining whether highly pathogenic HIV-1 variants utilize HP68 more effectively thereby leading to increased virion production
3. Identifying other viral-host interactions important for HIV-1 capsid formation
4. Determining whether human HP68 polymorphisms influence susceptibility to HIV-1 infection or progression to AIDS
5. Understanding how HCV encapsidates its genome and why assembly of this virus is blocked in cultured cell lines
6. Establishing novel cell-free systems to study assembly of other viruses that cause diseases relevant to public health
7. Understanding the enzymatic activity and function of endogenously expressed proteins in the APOBEC family, which includes cytidine deaminases that act as restriction factors.
Industrial Relevance
Potential for discovery of novel targets for inhibition of virus production
Keywords
COS Keywords:
AIDS, Allergy, Biochemical Markers, Biochemistry, Cell Biology, Emergency Health Services, Hepatitis, HIV, Immunoprecipitation, Infectious Diseases or Agents, Pathobiology, Physiology, Public Health, Retrovirus, Sexually Transmitted Diseases, Viral Infections, Virology.Additional Terms:
AIDS, Assembly, Biochemistry, Capsid, Cell Free System, HBV, HCV, Hepatitis B, Hepatitis C, Human Immunodeficiency Virus, Immunoprecipitation, Membrane Targetting, Molecular Chaperone, Retrovirus, Virology, Virus, Virus Assembly, Virus Formation, Virus Host Interaction, Virus Infection, Virus Production.Languages
(Reading, Writing, Speaking)
English: (Fluent, Fluent, Fluent)
French: (Functional, Functional, Functional)
Honors and Awards
2007, Annual Teaching Award,
Dept. of Pathobiology,
University of Washington School of Public Health
2002, First Annual Teaching Award,
Department of Pathobiology,
University of Washington School of Public Health
2001, Science in Medicine New Investigator Award,
University of Washington, Department of Medicine
1990, Honorary Election to the Alpha Omega Alpha Society,
University of California, San Francisco
1987, American Medical Women's Association Award,
University of Massachusetts Medical School
1982-1985,
National Research Service Award,
National Institutes of Health (NIH)
1980, Phi Beta Kappa,
Swarthmore College
1979, Distinction in Biology,
Swarthmore College
1978, Sigma Xi
Swarthmore College
Previous Positions
1999, Adjunct Assistant Professor,
University of California, San Francisco,
School of Medicine,
Physiology
1999-2005, Assistant Professor,
University of Washington,
School of Public Health and Community Medicine,
Pathobiology
1999-2005, Adjunct Assistant Professor,
University of Washington,
School of Public Health and Community Medicine,
Pathobiology
1994-1999, Assistant Research Physiologist,
University of California, San Francisco,
School of Medicine,
Physiology
1991-1999, Assistant Clinical Professor,
University of California, San Francisco,
School of Medicine,
Medicine
1991-1999, Attending Physician,
University of California, San Francisco,
School of Medicine,
Medicine,
Emergency Medical Services
Funding Received
- National Institutes of Health (NIH): Understanding the role of cellular factors in the HIV-1 capsid assembly pathway, $1,125,000, 2007 to 2012.
- NIAID: Cell-free VEE assembly system and alphavirus drug, $275,000, 2005 to 2008.
- United States Department of Defense (DOD): Novel viral agent identification and treatment, $223,000, 2005 to 2006.
- Puget Sound Partners for Global Health: Hepatitis C Pilot Project, $50,000, 2003 to 2004.
- American Foundation for AIDS Research: Vif-Gag complexes in cells: Effect of a host factor, $75,000, 2002 to 2003.
- National Institutes of Health (NIH): Role of a host protein in HIV particle formation, $900,000, 2002 to 2007.
- University of Washington CFAR: Comparing Retroviral Capsid Assembly: Role of a host factor, $60,000, 2000 to 2002.
- Pediatric AIDS Foundation: Regulation of HIV Maturation in a Cell-Free System, $192,000, 1998 to 2000.
- National Institutes of Health (NIH): Assembly of HIV Capsids in a Cell Free System, $510,000, 1997 to 2002.
- National Institutes of Health (NIH): Cytosolic Chaperones and Viral Assembly, $88,150, 1994 to 1997.
Publications
- Klein KC, Reed JC, Lingappa JR (2007) Intracellular destinies: degradation, targeting, assembly, and endocytosis of HIV Gag, AIDS Reviews, 9, 150-61
- Thielen BK, Klein KC, Walker LW, Rieck M, Buckner JH, Tomblingson GW, Lingappa JR (2007) T cells contain an RNase-insensitive inhibitor of APOBEC3G, PLoS Pathogens, 3 (9), e135
- Dooher JE, Reed JC, Schneider BL, Lingappa JR (2007) Host ABCE1 is at plasma membrane HIV assembly sites and its dissociation from Gag is linked to subsequent events of virus production, Traffic, 8 (3), 195-211
- Lingappa JR, Dooher JE, Newman MA, Kiser PK, and Klein KC (2006) Basic residues in the Nucleocapsid domain of Gag are required for interaction of HIV-1 gag with ABCE1 (HP68), a cellular protein important for HIV-1 capsid assembly, Journal of Biological Chemistry, 281 (7), 3773-84
- Klein KC, Dellos SR, Lingappa JR (Jun 2005) Identification of residues in the hepatitis C virus core protein that are critical for capsid assembly in a cell-free system., Journal of Virology, 79 (11), 6814-26
- Lingappa VR, Lingappa JR (May 2005) Recent insights into biological regulation from cell-free protein-synthesizing systems., Mt Sinai Journal of Medicine, 72 (3), 141-60
- Lingappa JR, Newman MA, Klein KC, Dooher JE (Mar 2005) Comparing capsid assembly of primate lentiviruses and hepatitis B virus using cell-free systems, Virology, 333 (1), 114-23
- Newman EN, Holmes RK, Craig HM, Klein KC, Lingappa JR, Malim MH, Sheehy AM (Jan 2005) Antiviral function of APOBEC3G can be dissociated from cytidine deaminase activity., Current Biology, 15 (2), 166-70
- Dooher JE, Lingappa JR, Cell-free systems for capsid assembly of primate lentiviruses from three
different lineages, Journal of Medical Primatology, 33(5-6), 272-80, Oct 2004
- Dooher JE, Pineda MJ, Overbaugh J, Lingappa JR, Characterization of virus infectivity and cell-free capsid assembly of
SIVMneCL8, Journal of Medical Primatology, 33(5-6), 262-71, Oct 2004
- Klein KC, Polyak SJ, Lingappa JR, Unique features of hepatitis C virus capsid formation revealed by de novo
cell-free assembly, Journal of Virology, 78(17), 9257-69, Sep 2004
- Dooher JE, Lingappa JR, Conservation of a stepwise, energy-sensitive pathway involving HP68 for, Journal of Virology, 78(4), 1645-56, February 2004
- Zimmerman C, Klein KC, Kiser PK, Singh AR, Firestein BL, Riba SC, Lingappa JR, Identification of a host protein essential for assembly of immature HIV-1
capsids, Nature, 415(6867), 88-92, January 2002
- Singh AR, Hill RL, Lingappa JR, Effect of mutations in Gag on assembly of immature human immunodeficiency
virus type 1 capsids in a cell-free system, Virology, 279(1), 257-70, Jan 2001
- Lingappa JR, Hill RL, Wong ML, Hegde RS, A multistep, ATP-dependent pathway for assembly of human immunodeficiency virus capsids in a cell-free system, Journal of Cell Biology, 136(3), 567-81, February 1997
- Lingappa JR, Martin RL, Wong ML, Ganem D, Welch WJ, Lingappa VR, A eukaryotic cytosolic chaperonin is associated with a high molecular weight intermediate in the assembly of hepatitis B virus capsid, a multimeric particle, Journal of Cell Biology, 125(1), 99-111, April 1994
- Lingappa JR, Zigmond RE, Pineal transplants in oculo: limitations on the ability of collateral sprouts of foreign neurons to establish normal function, Journal of Neuroscience, 7(11), 3525-8, November 1987
- Lingappa JR, Zigmond RE, A Histochemical Study of the Adrenergic Innervation of the Rat Pineal
Gland: Evidence for Overlap of the Innervation From the Two Superior
Cervical Ganglia and for Sprouting Following Unilateral
Denervation., Neuroscience, 21(3), 893-902, Jun 1987
- Lingappa VR, Lingappa JR, Blobel G, Signal sequences for early events in protein secretion and membrane assembly, Annals of the New York Academy of Sciences, 343, 356-61, 1980
- Lingappa VR, Lingappa JR, Blobel G, Chicken Ovalbumin Contains An Internal Signal Sequence., Nature, 281(5727), 117-21, Sep 1979
- Lingappa VR, Lingappa JR, Prasad R, Ebner KE, Blobel G, Coupled cell-free synthesis, segregation, and core glycosylation of a secretory protein, Proceedings of the National Academy of Sciences (USA), 75(5), 2338-42, May 1978
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Last Updated: 11/14/2007
COS Expertise ID #538994
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