the initial findings for virus-antiviral antibody immune complexes, CD8 CTL-mediated killing, CD4 help for maintaining CD8 activity, fine mapping of T cell epitopes, MHC restriction;determination that peptides of 9 aa or less fit into the MHC class I groove, expansion, contraction and memory of antigen-specific CD8, CD4 and B lymphocyte responses, use of adoptive transfer of memory T cells to abort persistent infection, analysis of the immunologic synapse in vivo and the ability of non-lytic persistent viruses to cause disease by altering differentiated function of the infected cell without affecting its vital function. Recently, we and others have uncovered host immune response modulating molecules induced by virus that suppressed the T cell response(s) required to purge virus. Remarkably, the use of antibody therapy to neutralize such host molecules resurrected function to non-functional (exhausted) T cells so these T cells were now able to control the viral infection. Immunosurveillance and removing virally infected cells is primarily the function of T cells. We made the stunning observation that IL-10 determines viral clearance or persistence in vivo and that antibody blockade of IL-10 receptor (R) during persistent infection when T cells are non-functional restores their function, brings back deleted subset of CD8 killer T cells, purges virus and controls the viral infection. We propose to define the mechanism(s) involved, determine the host cells producing IL-10, optimize therapy and study combined effect with addition of antibodies to IL-10R and PD-1 and, lastly, analyze the use of virus-induced blockade of host immunosuppressive molecules as strategies for vaccine therapy of persistent viral infections. Project Description Page 6

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI009484-43
Application #
8204803
Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
Project Start
1977-09-01
Project End
2013-05-14
Budget Start
2012-01-01
Budget End
2013-05-14
Support Year
43
Fiscal Year
2012
Total Cost
$464,322
Indirect Cost
$219,297
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Teijaro, John R; Studer, Sean; Leaf, Nora et al. (2016) S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification. Proc Natl Acad Sci U S A 113:1351-6
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Baccala, Roberto; Welch, Megan J; Gonzalez-Quintial, Rosana et al. (2014) Type I interferon is a therapeutic target for virus-induced lethal vascular damage. Proc Natl Acad Sci U S A 111:8925-30
Walsh, Kevin B; Teijaro, John R; Brock, Linda G et al. (2014) Animal model of respiratory syncytial virus: CD8+ T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy. J Virol 88:6281-93
Teijaro, John R; Walsh, Kevin B; Long, James P et al. (2014) Protection of ferrets from pulmonary injury due to H1N1 2009 influenza virus infection: immunopathology tractable by sphingosine-1-phosphate 1 receptor agonist therapy. Virology 452-453:152-7
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