Varicella-zoster virus (VZV), a human herpesvirus, causes varicella (chickenpox) and herpes zoster (singles). VZV disease produces serious morbidity and can be life-threatening in otherwise healthy adults, the elderly, and in human immunodeficiency virus (HIV)-infected, cancer and transplant patients. Our objective is to define immunogenic proteins and host factors affecting cellular immune responses to VZV in experiments which will be relevant to VZV vaccine design and optimal use of live attenuated varicella vaccine. Helper and cytotoxic T-cell (CTL) recognition of structural/regulatory gene products (ORF4, ORF10, ORF61, and ORF63) will be evaluated using VZV-vaccinia recombinants. Since memory T-cells recognize gp I, gp IV and IE62 protein, immunodominant regions will be identified with recombinants that express truncated forms of each protein. T-cell epitopes will be mapped using peptides that fit proposed overlapping CD4+ and DC8+ T-cell motifs and expressing the sequences in vaccinia. The dendritic cell system will be developed as an in vitro method to determine whether the same VZV proteins or peptides that elicit T-cell recognition after natural infection in vivo are active primary immunogens when presented as purified proteins or related peptides to naive T-cells. Since the expression of viral proteins in infected cells does not predict their immunogenicity, this method has broad potential value for designing protein or peptide vaccines. Genetic factors affecting the host response will be determined by analyzing T- cell recognition of glycoproteins and IE62 protein in donors of known MHC phenotype. Age-related factors influencing the primary host response will be assessed by comparing VZV specific CD4+ and DC8+ responses in children and adults immunized with varicella vaccine. Cytokine production will be investigated to determine whether adults have a relative failure to prime Th1-like CD4+ T-cells or a relative predominance of the Th3-like subset which could downregulate essential Th1-like responses. Whether the increased susceptibility to VZV reactivation in elderly individuals correlates with a quantitative decrease in T-cells that recognize VZV proteins and/or in the relative predominance of Th1 or Th2-like CD4+ T-cell responses will be evaluated. Understanding cytokine responses to viral antigens could yield new insights about their potential value as vaccine components. Finally, because the widespread use of varicella vaccine will reduce opportunities to boost VZV immunity by re-exposure during the annual varicella epidemics, it is important to investigate whether there ar any age- related obstacles to using the vaccine to enhance T-cell immunity. Helper and CTL recall responses will be evaluated in children and adults with vaccine-induced immunity who ar re-vaccinated after 4-10 years. The comparative efficacy of immunization for enhancing natural immunity will be assessed in younger and elderly adults since VZV vaccines may have therapeutic value for preventing herpes zoster. Investigating VZV immunity is directly relevant to clinical practice because current evidence is that a single vaccine preparation will be effective optimally in all clinical circumstances.
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