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

HSV 的细胞毒性 T 细胞反应：HIV 感染者

• 批准号: 6847118
• 负责人: Lawrence Corey
• 金额: $ 32.83万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847118
• 关键词: AIDS therapy; Alphaherpesvirinae; HIV infections; Herpesviridae disease; cellular immunity; combination chemotherapy; cytokine; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; helper T lymphocyte; human subject; latent virus infection; opportunistic infections; patient oriented research; virus infection mechanism; virus protein; virus replication

Herpes simplex virus (HSV) is ubiquitous among HIV+ persons and is an important opportunistic infection (OI), influencing both the clinical progression of HIV as well as enhancing its transmission and acquisition. Our initial studies defining T cell responses to HSV among HIV+ persons have indicated that HSV-specific CD8+ T cells play a prominent role in the control of HSV 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 differs from 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. Specific Aim #1 will utilize recently developed technologies including ELISpot, intracellular cytokine staining and HLA/peptide tetramers, to quantitate the HSV-specific CD8+ T cell response in HSV-infected persons with acute HIV infection treated early with highly active antiretroviral therapy. These persons should have relatively intact CD4+ T cell responses to HSV and we will test the hypothesis that the rate of HSV reactivation is influenced by the frequency of HSV-specific CD8+ T cells prior to HIV acquisition. We will also measure CD8+ T cell responses in HIV- negative persons with primary HSV infection to test the hypothesis that the memory CD8+ set point established during primary infection is inversely correlated with subsequent reactivation rates of HSV even in the immunocompetent person. Specific Aim #2 will quantitate the local HSV-specific CD8+ T cell response by T cell clonotype specific assays to determine if the quantitative circulating CD8+ T cell response to HSV is directly correlated with the quantitative mucosal CD8+ T cell response. Local CD8+ T cell responses will be compared among HIV+ persons with low versus high frequencies of pCTL and in persons with low versus high rates of HSV reactivation. Specific Aim #3 will determine if the effector mechanisms (killing and cytokine/chemokine release) utilized by lesion-derived HSV-specific CD8+ T cells between HIV+ and HIV-negative persons. These 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.

单纯疱疹病毒（HSV）在艾滋病毒+人中无处不在，是重要的机会感染（OI），既影响艾滋病毒的临床进展，又可以增强其传播和获取。 我们的最初研究定义了HIV+人中T细胞对HSV的反应的最初研究表明，HSV特异性CD8+ T细胞在控制HSV的HSV重新激活速率中起着重要的作用。 令我们惊讶的是，HAART治疗同时增加了HSV特异性CD4+ T细胞反应，对HSV重新激活率几乎没有影响，这表明HSV与这方面的其他疱疹病毒感染有所不同。 我们提出的研究旨在定义系统性和局部HSV特异性CD8+ T细胞反应与HSV的粘膜重新激活率之间的关系。 具体目的＃1将利用最近开发的技术，包括ELISPOT，细胞内细胞因子染色和HLA/肽四聚体，在HSV感染的HIV感染患者中量化HSV特异性CD8+ T细胞反应，并早期治疗了高度活性抗雷神治疗的急性HIV感染。 这些人应具有相对完整的CD4+ T细胞对HSV的反应，我们将检验以下假设：HSV重新激活的速率受HIV获取之前HSV特异性CD8+ T细胞的频率的影响。 我们还将测量原发性HSV感染的HIV阴性人员中的CD8+ T细胞反应，以检验以下假设：在原发性感染期间建立的记忆CD8+设定点即使在免疫能力的人中也与随后的HSV重新激活率成反比。 特定的目标＃2将通过T细胞clonotype特异性测定法对局部HSV特异性CD8+ T细胞响应进行定量，以确定定量循环CD8+ T细胞对HSV的响应是否与定量粘膜CD8+ T细胞反应直接相关。 在PCTL低频与高频的HIV+患者中，将比较局部CD8+ T细胞的反应，以及HSV重新激活率低的人。 特定的目标＃3将确定因病变衍生的HSV特异性CD8+ T细胞在HIV+和HIV阴性人之间使用的效应机制（杀死和细胞因子/趋化因子释放）。 这些提出的研究将提供有关HSV特异性CD8+ T细胞反应在OI的粘膜重新激活中起作用的新信息，并为提供新颖的治疗方法提供疾病管理的潜力。