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

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
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Scripps Research Institute
La Jolla
United States
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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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Burri, Dominique J; Pasquato, Antonella; da Palma, Joel Ramos et al. (2013) The role of proteolytic processing and the stable signal peptide in expression of the Old World arenavirus envelope glycoprotein ectodomain. Virology 436:127-33
Oldstone, Michael B A (2013) Lessons learned and concepts formed from study of the pathogenesis of the two negative-strand viruses lymphocytic choriomeningitis and influenza. Proc Natl Acad Sci U S A 110:4180-3
Hara, Yuji; Balci-Hayta, Burcu; Yoshida-Moriguchi, Takako et al. (2011) A dystroglycan mutation associated with limb-girdle muscular dystrophy. N Engl J Med 364:939-46
Popkin, Daniel L; Teijaro, John R; Lee, Andrew M et al. (2011) Expanded potential for recombinant trisegmented lymphocytic choriomeningitis viruses: protein production, antibody production, and in vivo assessment of biological function of genes of interest. J Virol 85:7928-32
Krebs, Philippe; Crozat, Karine; Popkin, Daniel et al. (2011) Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice. Blood 117:6582-8

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