Immune Correlates of HSV-2 Disease Severity

HSV-2 疾病严重程度的免疫相关性

• 批准号: 6365452
• 负责人: David M Koelle
• 金额: $ 26.03万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6365452
• 关键词: Herpesviridae vaccine; MHC class I antigen; antigen antibody reaction; case history; cell mediated lymphocytolysis test; cellular immunity; clinical research; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; expression cloning; genital herpes; helper T lymphocyte; herpes simplex virus 2; human subject; vaccine development; virus antigen

A vaccine will be required to control the ongoing epidemic of genital herpes. Most severe, recurrent genital herpes is due to herpes simplex virus type 2 (HSV-2). Current vaccines for HSV-2 have failed or had partial activity in selected patient populations. Cellular immune responses to (HSV-2) are important in controlling infection. The induction of cellular immunity, both CD8 CTL capable of killing virally infected cells and/or halting replication,- and CD4 helper cells capable of supporting CD8 and antibody effectors, is likely to be a characteristic of a successful vaccine. The goal of this proposal is to identify targets of the cellular immune system to assist in the rational design of a vaccine. The first Aim is to identify the HSV-2 antigens-and epitopes recognized by CD8 CTL, and to place these responses in a hierarchy of immunodominance with regards to population prevalence and effector cell number. A novel expression cloning method is used for antigen discovery. To study immune responses associated with effective immunity, subjects will be carefully selected to have extremely mild HSV-2 infection as measured objectively by genital shedding rates as well as by clinical history. To reduce analytical complexity, some assays will focus on the commonest human HLA type. The second Aim is to determine if quantitative or qualitative difference in HSV-specific CD8 responses can be detected between groups of carefully characterized subjects with mild or severe chronic HSV-2 infection. Antigen- and epitope-specific assays will be applied to blood samples. The third Aim is to determine the prevalence and magnitude of CD4 helper responses to the HSV-2 antigens that are identified in Aims 1 and 2 as potentially immunodominant and/or associated with mild infection. Overall CD4 responses to HSV-2 will also be compared between the subject groups with defined HSV-2 disease severity. The results may assist in rational design of a HSV-2 vaccine or the monitoring of HSV-2 vaccine trials or immune responses modifiers that are active for recurrent HSV-2. The data will also reveal the in vivo effects of HSVencoded immune evasion genes on the CD8 CTL response within the natural host.

需要一种疫苗来控制生殖器疱疹的持续流行。最严重的复发性生殖器疱疹是由 2 型单纯疱疹病毒 (HSV-2) 引起的。目前的 HSV-2 疫苗在选定的患者群体中已经失败或具有部分活性。针对 (HSV-2) 的细胞免疫反应对于控制感染非常重要。细胞免疫的诱导，包括能够杀死病毒感染细胞和/或停止复制的 CD8 CTL，以及能够支持 CD8 和抗体效应子的 CD4 辅助细胞，可能是成功疫苗的特征。该提案的目标是确定细胞免疫系统的目标，以协助疫苗的合理设计。第一个目标是鉴定 CD8 CTL 识别的 HSV-2 抗原和表位，并将这些反应置于关于群体流行率和效应细胞数量的免疫优势层次中。一种新的表达克隆方法用于抗原发现。为了研究与有效免疫相关的免疫反应，将仔细选择受试者，根据生殖器脱落率和临床病史客观测量，患有极轻度 HSV-2 感染。为了降低分析复杂性，一些检测将重点关注最常见的人类 HLA 类型。第二个目的是确定在经过仔细表征的轻度或重度慢性 HSV-2 感染受试者组之间是否可以检测到 HSV 特异性 CD8 反应的定量或定性差异。抗原和表位特异性检测将应用于血液样本。第三个目标是确定 CD4 辅助细胞对 HSV-2 抗原反应的普遍性和程度，这些抗原在目标 1 和 2 中被鉴定为潜在的免疫显性和/或与轻度感染相关。还将比较具有明确 HSV-2 疾病严重程度的受试者组之间对 HSV-2 的总体 CD4 反应。结果可能有助于合理设计 HSV-2 疫苗或监测 HSV-2 疫苗试验或对复发性 HSV-2 有效的免疫反应调节剂。这些数据还将揭示 HSV 编码的免疫逃避基因对自然宿主内 CD8 CTL 反应的体内影响。