This is a corrected and revised resubmission to study virus-induced immune response modulating molecule(s) that suppress the virus-specific T cell response that is required to clear virus, and the use of neutralizing antibodies to such virus-induced host suppressor molecules to resurrect the exhausted T cells which then can control the virus infection. Realizing that viruses persist and in doing so cause disease is one of the major accomplishments in virology. The principles of how this occurs and how to prevent and treat persistent infections continues as the topic for this productive research grant for which funding of the 40th to 45th year is requested. Our tact is to use lymphocytic choriomeningitis virus (LCMV) infection of its natural host, the mouse, to uncover principles involved. The success of this approach (by ourselves and others) provided 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.
A major public health concern is persistent virus infection and a major biomedical challenge is the understanding and design of successful therapy to counteract these infections. Such infections are characterized, in part, by T cell exhaustion, a state where virus-specific T cells no longer function to control the virus. We identify a host gene product, IL-10, induced by virus to suppress the host's immune response, develop and design therapy to neutralize IL-10 with antibodies during the state of T cell exhaustion thereby resurrecting antiviral T cell function which is able to limit or cure the persistent infection.
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