Jaisri Lingappa, M.D., Ph.D.
Assistant Professor of Pathobiology
Adjunct Assistant Professor of Medicine

CONTACT INFORMATION
University of Washington
Box 357238
Seattle, WA 98105-7238

Phone: (206) 616-9305
Fax: (206) 543-3873
E-mail: jais@u.washington.edu 

CURRENT RESEARCH INTERESTS

The Lingappa laboratory uses a cell biological approach to study the assembly of viral capsids, the protein shells that protect viral genomes. Viruses must negotiate the complicated internal environment of a hostile mammalian cell in order to assemble capsids that are needed to release progeny virus from the cell and spread the viral infection throughout the host. Exactly how this occurs remains poorly understood. 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 factors present in the host to promote efficient assembly of their progeny virions.

My lab is interested in identifying host cell factors that are critical for viral capsid formation, and understanding their mechanisms of action. For this purpose, we have established cell-free systems for viral capsid assembly, in which cell extracts are used to faithfully reconstitute capsid formation. Events that occur extremely rapidly and efficiently in cells occur less efficiently in cell-free systems, allowing them to be identified, manipulated, and dissected. After we identify cellular machinery using our cell-free systems, we turn to cellular systems of capsid formation to verify our findings. To date, we have established cell-free systems for the assembly of human immunodeficiency virus type 1 (HIV-1), HIV-2, hepatitis B virus (HBV), and hepatitis C virus (HCV) capsids. We have demonstrated that all of these viral capsids assemble via step-wise, energy-dependent pathways involving host factors. In the case of HIV-1, we identified a host factor we term HP68 that binds to assembling chains of the capsid protein Gag in the cell-free system as well as in HIV-1 infected T cells. Genetic, biochemical, and morphologic studies in mammalian cells and the cell-free system indicate that HP68 plays an essential role in post-translational events of immature HIV-1 capsid assembly. 

Current projects in my laboratory include (1) understanding the molecular determinants of the Gag-HP68 virus-host interaction, (2) identifying other viruses that utilize the HP68-dependent assembly pathway, (3) utilizing knockout approaches to better understand the role of HP68 in capsid assembly, and (4) studying host factors involved in assembly of HCV and HBV capsids. Future directions include (1) identifying how the cellular factor HP68 uses energy to promote viral capsid assembly, (2) examining whether highly pathogenic viral 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, and (5) establishing novel cell-free systems to study assembly of other viruses that cause diseases relevant to public health.

 

PUBLICATIONS