IMMUNITY & VIRAL REPLICATION IN CHILDREN WITH VARICELLA

水痘-带状疱疹病毒(VZV)，一种人类疱疹病毒，引起水痘 (水痘)和带状疱疹(单身)。VZV病产生严重 在其他健康的成年人中，发病率和可能危及生命， 老年人和感染人类免疫缺陷病毒(HIV)的人中，癌症和 移植病人。我们的目标是定义免疫原性蛋白和 宿主因素对VZV细胞免疫应答影响的实验研究 这将与VZV疫苗的设计和活疫苗的最佳使用相关 水痘减毒疫苗。辅助性和细胞毒性T细胞(CTL) 结构/调控基因产物的识别(ORF4、ORF10、ORF61、 和ORF63)将使用VZV-痘苗重组体进行评估。自.以来 记忆T细胞识别免疫显性的GP I、GP IV和IE62蛋白 将用表达截短形式的重组体来识别区域 每种蛋白质的。将使用符合以下条件的多肽绘制T细胞表位图 建议重叠的CD4+和DC8+T细胞基序并表达 牛痘病毒的序列。树突状细胞系统将发展为 一种体外检测相同的VZV蛋白或多肽的方法 在体内自然感染后引起T细胞识别的细胞是活跃的 以纯化蛋白或相关蛋白形式呈现的主要免疫原 多肽转化为幼稚的T细胞。由于病毒蛋白在体内的表达 被感染的细胞不能预测它们的免疫原性，这种方法有 设计蛋白质或多肽疫苗具有广阔的潜在价值。遗传 影响寄主反应的因素将通过分析T- 已知MHC供体对糖蛋白和IE62蛋白的细胞识别作用 表型。影响主要宿主反应的年龄相关因素 将通过比较VZV特异性的CD4+和DC8+反应来评估 儿童和成人接种水痘疫苗。细胞因子 将对生产进行调查，以确定成年人是否有 相对未能激活Th1样CD4+T细胞或其亲属 Th3样亚群的优势可能下调Essential 类Th1反应。VZV易感性的增加是否 老年人的重新激活与数量上的 识别VZV蛋白和/或亲缘关系的T细胞减少 将评估Th1或Th2样CD4+T细胞反应的优势。 了解细胞因子对病毒抗原的反应可能会产生新的 对其作为疫苗成分的潜在价值的洞察。最后， 因为水痘疫苗的广泛使用会减少机会 在一年一度的水痘期间通过再次暴露来提高VZV免疫力 流行病，重要的是要调查是否有任何年龄- 使用疫苗增强T细胞免疫的相关障碍。 助手和CTL召回反应将在儿童和成人中进行评估 有疫苗诱导免疫的人，在4-10年后重新接种。这个 免疫对增强自然免疫力的比较效果将 在年轻人和老年人中进行评估，因为VZV疫苗可能有 预防带状疱疹的治疗价值。调查VZV 免疫力与临床实践直接相关，因为目前 有证据表明，单一的疫苗制剂最有效。 在所有的临床情况下。

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.