The long term goals of this research are to define the events that take place during interaction of herpes simplex virus (HSV) with the host immune system and the mechanisms by which the virus attempts to evade or dampen host immunity. In this proposal our specific aims are: l. To define the role of complement component C3 in the host immune response to HSV and heterologous antigens expressed by recombinant HSV by measurement of specific B and T cell responses to different HSV strains in C3 -/- and +/+ strains of mice, by defining the viral requirements for C3-enhancement of the Ig response and for the local induction of C3, by measurement of protective effects of viral vaccines against virulent virus challenge in C3 -/- and +1+ mice, by construction of viruses that express C3 to determine if this complements the defect in immune response in C3 knock-out mice, by determining if expression of C3 from a viral vector enhances the immune response to the virus in C3 wt mice, and by comparing the enhancement of the immune response when C3 is expressed in another cell, in the same cell, or fused to the test antigen. 2. To test the effect of glycoprotein C (gC) and the viral Fc receptor on the host immune response by defining the host immune response in normal mice to gC-negative and gC-positive viruses, by defining the host immune response in C3 knock-out mice to gC-negative and gC-positive viruses, and by constructing HSV strains that are defective for the Fc receptor activity and examining the host immune response to these viruses. 3. To define the role of HSV ICP47, which blocks TAP transporter function in human cells, in affecting the host immune response and viral pathogenesis by studying infections in transgenic mice bearing human TAP genes -replacing the murine TAP genes. These studies will measure the effect of ICP47 on viral infection, induction and effector function of CD8+ CTLs, and on immunization of mice. 4. Measurement of the effect of bovine papilloma virus E6 and other viral gene products on CD4+ T cell responses to HSV to determine if these gene products inhibit class II presentation. The significance of the preliminary results and the proposed experiments is three- fold: l) These studies provide the first evidence that innate immunity plays a role in the adaptive immune response to viruses. 2) The preliminary results suggest-new mechanisms by which HSV could block the host immune response. 3) The results suggest new adjuvant approaches or ways to increase the immune response to viral vaccines. These studies may define new basic mechanisms operating in the immune system and better ways to develop. vaccines a against HSV and other viruses.
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