Primary varicella-zoster viral (VZV) infection in healthy subjects allows the analysis of the host response during a systemic human herpes viral infection in relation to events in pathogenesis, e.g., viremia, and disease severity. Activation of the interferon system and increase in circulating large lymphocytes were the earliest immunologic changes detected in our initial study of early VZV immunity. Large granular lymphocytes are mediators of natural killer (NK) cell activity and can be induced by interferon (IFN). In addition to its direct antiviral effect, an increase in NK cells which can lyse VZV infected cells prior to specific immunity could explain the role of IFN in primary VZV. NK activity will be analyzed by phenotypic markers for NK cells and by lysis of the NK target cell line, K562. Many large lymphocytes during primary VZV were DR positive, activated T-lymphocytes. DR expression is inducible by gamma IFN which was present in acute VZV. In the next phase of the study, interleukin 2 (I1-2), another immunomodulating substance important in initiation of immunity, will be investigated with assays for serum I1-2, I1-2 receptors on T-lymphocytes and in vitro I1-2 production by T-lymphocytes. Early VZV specific T-lymphocyte proliferation correlated with milder clinical infection in our initial study. The role of VZV specific T-lymphocyte cytotoxicity in the restriction of VZV replication will be examined using VZV-infected donor EBV-transformed peripheral blood mononuclear cells as target cells. Natural VZV immunity will be compared with varicella vaccine induced immunity in healthy subjects. Our initial studies indicated diminished humoral and cellular immunity to two major VZV glycoproteins, gp90/58 and gp118, and to a non-glycosylated protein, p170, in vaccinees. The persistence of immunity to these proteins will be analyzed after vaccination and natural immunity using assays of IgG, T-lymphocyte proliferation, responder cell frequency and of the functional capacities of """"""""memory"""""""" T-lymphocytes in assays of cytotoxicity and lymphokine production (I1-2, IFNg). The role of viremia in VZV pathogenesis was demonstrated with viral isolation from peripheral blood mononuclear cells obtained immediately after the appearance of the varicella exanthem. Viremia will be investigated durther using VZV monoclonal antibody reagents to detect VZV in peripheral blood mononuclear cells. Methods will be pursued which avoid the problem of non-specific binding of the reagents to activated peripheral blood cells.
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