Cytotoxic T-Cell Responses to HSV: HIV-Infected Persons

单纯疱疹病毒在HIV感染者中普遍存在，是一种重要的机会性感染。 (Ol)，既影响艾滋病毒的临床进展，也促进其传播和获得。 我们在HIV感染者中定义T细胞对HSV的反应的初步研究表明，HSV特异性 CD8T细胞在控制HIV患者粘膜部位HSV再激活中起着重要作用。在……里面 特别是，那些具有HSV特异性CD8 T细胞前体频率低的人具有较高的再激活率 单纯疱疹病毒。令我们惊讶的是，HAART疗法虽然增加了HSV特异性的CD4T细胞反应，但几乎没有什么效果 对HSV复活率的影响，表明HSV在这一点上不同于其他疱疹病毒感染 敬重。我们建议的研究旨在确定系统性和局部性HSV之间的关系。 HSV特异性CD8T细胞应答和粘膜复活率。在融资的初始阶段，我们 已经表明CD8 T细胞对HSV-2的反应比以前大得多 值得赞赏，而且个体之间存在显著差异。特殊目标#1使用ELISpot， 细胞内细胞因子染色和人类白细胞抗原/多肽四聚体定量检测HSV特异性CD8 T细胞 单纯疱疹病毒2型感染者的反应。我们的假设是，规模和广度增加的人 CD8T细胞反应的HSV再活化率将会降低。我们最近开发了 用一种新的量子点方法原位染色HSV特异性四聚体技术 结果表明，HSV特异性CD8T细胞持续存在于真皮-表皮交界处，并位于邻近的 这一区域的外周神经元；表明它们可能影响病毒的重新激活。我们建议的研究将 在原位评估这些HSV-2特异性CD8 T细胞的持久性，并确定它们的出口是否 与随后的病毒重新激活有关。HSV特异性的CD4和CD8T细胞在体内发生了变化 功能配置文件。具体目标3将是使用多参数流式细胞术来表征这些 功能缺陷。以上提出的研究将提供关于HSV特异性作用的新信息 CD8T细胞反应在OI的粘膜再激活中发挥作用，并提供了提供新的 疾病管理的治疗方法。

Herpes simplex virus (HSV) is ubiquitous among HIV+ persons and is an important opportunistic infection (Ol), influencing both the clinical progression of HIV as well as enhancing its transmission and acquisition. Our initialstudies defining T cell responses to HSVamong HIV+ persons have indicated that HSV-specific CD8+ T cells play a prominent role in the control of HSV reactivation at mucosal sites in HIV+ persons. In particular, those with low precursor frequencies of HSV-specific CD8+ T cells have high reactivation rates of HSV. To our surprise, HAART therapy, while increasing HSV-specific CD4+ T cell responses, had little effect upon HSV reactivation rates, indicating that HSV differsfrom other herpesvirus infections in this regard. Our proposed studies are directed at defining the relationship between systemic and local HSV- specific CD8+ T cell responses and mucosal reactivation rates of HSV. During the initial phase of funding we have shown that the breadth of the CD8+ T cell response to HSV-2 is much greater than previously appreciated and there is significant variability between individuals. Specific Aim #1 uses ELISpot, intracellular cytokine staining and HLA/peptide tetramers, to quantitate the HSV-specific CD8+ T cell response in HSV-2 infected persons. Our hypothesis is that persons with increased magnitude and breadth of the CD8+ T cell response will have reduced rates of HSV reactivation. We have recently developed the technique of in situ staining of HSV specific tetramers using a novel quantum dot methodology and have shown that HSV specific CD8+ T cells persist at the dermal-epidermal junction and are located contiguous to peripheral neurons in this area; suggesting they may influence viral reactivation. Our proposed studies will evaluate the persistence of these HSV-2 specific CD8+ T cells in situ and define whether their egress is associated with subsequent viral reactivation. HSVspecific CD4+ and CD8+ T cells have altered in vivo functional profiles. Specific Aim 3 will be to use multiparameter flow cytometry to characterize these functional deficits. The above proposed studies will provide novel information about the role HSV-specific CD8+ T cell responses play on mucosal reactivation of an OI and offer the potential for providing novel therapeutic approaches for disease management.