IMMUNOLOGICAL CONTROLS IN HSV LATENCY AND REACTIVATION

这项提案的总体目标将是确定 个体表型和功能定义的T淋巴细胞 控制宿主病毒三个不同阶段的亚群 感染单纯疱疹病毒(HSV)后的关系这个 将研究的阶段将是(I)从初级疫苗中清除病毒 感染部位，(Ii)在神经细胞中建立潜伏感染 局部感觉神经节，以及(Iii)病毒从潜伏状态重新激活 州政府。第一个目标将是确定出镜率和 免疫功能性单纯疱疹病毒特异性辅助者前体的频率 和局部淋巴组织中的细胞毒性T淋巴细胞 感染单纯疱疹病毒，并将研究扩展到免疫小鼠 继发性感染。这将在两个品系的近交系小鼠身上进行评估 对HSV感染表现出不同程度的先天抵抗力。 C57BL/6(H-2b)小鼠对HSV感染具有相对抵抗力，而 BALB/c(H-2d)小鼠为中度敏感。天生的抵抗力是 由基因决定的，并已被证明具有免疫学基础 在T淋巴细胞介导的免疫反应成分中。这 提示敏感菌株可能具有基本的免疫学特性 妨碍单纯疱疹病毒初始控制成功的缺陷 繁衍和传播。通过比较早期T淋巴细胞 在这两种毒株中，将有可能确定一种 潜在的T淋巴细胞介导的反应是导致这种情况的原因 观察。第二个目标将是确定T的作用 淋巴细胞反应在控制HSV增殖和清除HSV中的作用 感染的原发部位、潜伏期的建立和随后 将HSV从潜伏期重新激活。这一点将由 表型和功能定义的HSV特异性T细胞的过继转移 幼稚受者的淋巴细胞亚群，以及体内选择性耗竭 通过使用针对这些亚群的单抗进行治疗 与每个功能亚集相关的分化同种抗原。这个 第三个目标将是确定HSV病毒糖蛋白的作用 以及这些组件以何种模式呈现给 产生有效应答的单纯疱疹病毒特异性T淋巴细胞。

The overall aim of this proposal will be to determine the role of individual phenotypically and functionally defined T lymphocte subpopulations in the control of three distinct stages of the host-virus relationship following infection with herpes simplex virus (HSV). The stages to be studied will be (i) the clearance of virus from the primary site of infection, (ii) the establishment of latent infection in neurons of local sensory ganglia, and (iii) the reactivation of virus from the latent state. The first objective will be to determine the rate of appearance and frequency of precursors of immunologically functional HSV-specific helper and cytotoxic T lymphocytes in local lymphoid tissue following a local infection with HSV, and to extend the study to immunized mice responding to a secondary infection. This will be assessed in two strains of inbred mice which exhibit different levels of innate resistance to HSV infection. C57BL/6 (H-2b) mice are relatively resistant to infection with HSV, while BALB/c (H-2d) mice are moderately sensitive. Innate resistance is genetically determined, and has been shown to have an immunological basis in the T lymphocyte-mediated component of the immune response. This suggests that the sensitive strains may have a fundamental immunological deficiency that precludes the successful initial control of HSV multiplication and dissemmination. By comparing the early T lymphocyte repsonse in these two strains, it will be possible to determine whether an underlying T lymphocyte-mediated response is responsible for this observation. The second objective will be to determine the role of the T lymphocyte response in the control of HSV multiplication and clearance from the primary site of infection, the establishment of latency and subsequent reactivation of HSV from the latent state. This will be studied by the adoptive transfer of phenotypically and functionally defined HSV-specific T lymphocyte subsets to naive recipients, and by selective in vivo depletion of these subsets by treatment with monoclonal antibodies specific for differentiation isoantigens associated with each funcitonal subset. The third objective will be to determine the role of HSV viral glycoproteins involved, and the mode in which these components are presented to the HSV-specific T lymphocytes that results in an effective response.