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: 7111175
• 负责人: Lawrence Corey
• 金额: $ 35.28万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111175
• 关键词: Acquired Immunodeficiency Syndrome; Area; Ascaridil; CD4 Positive T Lymphocytes; CD8 Antigens; CD8B1 gene; Clinical; Cutaneous; Cytotoxic T-Lymphocytes; Dermal; Disease Management; Epidemic; Exhibits; Flow Cytometry; Frequencies; Funding; Genes; Genetic Polymorphism; HIV; HIV-1; Herpesviridae Infections; Highly Active Antiretroviral Therapy; Homing; Human Herpesvirus 2; Immune; Immunity; Immunobiology; In Situ; Individual; Infection; Infiltration; Interferon Type II; Lesion; Lymphocyte; Manuscripts; Mediator of activation protein; Methodology; Neurons; Opportunistic Infections; PVRL1; Patients; Peptides; Peripheral; Persons; Phase; Plasma; Play; Progress Reports; Publishing; Quantum Dots; RNA; Rate; Resolution; Role; Simplexvirus; Skin; Snow; Staining method; Stains; Stem cell transplant; T-Lymphocyte; Techniques; Tissues; Vaccine Research; Viral; Virus; acquired immunity; chemokine; cytokine; high voltage electron microscopy; in vivo; killings; mucosal site; nectin; novel; novel therapeutics; progesterone 11-hemisuccinate-(2-iodohistamine); receptor; response; transmission process

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.

单纯疱疹病毒（HSV）在HIV阳性人群中普遍存在，是一种重要的机会性感染 (Ol)影响HIV的临床进展以及增强其传播和获得。 我们的初步研究确定了HIV阳性者中T细胞对HSV的反应，表明HSV特异性T细胞对HSV的反应是由HIV阳性者的T细胞对HSV的反应决定的。 CD 8 + T细胞在HIV+患者粘膜部位的HSV再活化控制中发挥重要作用。在 特别地，具有HSV特异性CD 8 + T细胞的低前体频率的那些具有高的再活化率， HSV。令我们惊讶的是，HAART治疗虽然增加了HSV特异性CD 4 + T细胞应答， 对HSV再激活率的影响，表明HSV与其他疱疹病毒感染不同， 请注意。我们提出的研究旨在确定系统性和局部HSV之间的关系， HSV特异性CD 8 + T细胞应答和粘膜再活化率。在融资初期，我们 已经表明，CD 8 + T细胞对HSV-2应答的广度比以前大得多， 这是值得赞赏的，个体之间存在显著差异。特定目标#1使用ELISpot， 细胞内细胞因子染色和HLA/肽四聚体，以定量HSV特异性CD 8 + T细胞 HSV-2感染者的反应。我们的假设是，人们的规模和广度增加， 的CD 8 + T细胞应答将具有降低的HSV再活化率。我们最近开发了 使用新量子点方法原位染色HSV特异性四聚体的技术， 显示HSV特异性CD 8 + T细胞持续存在于真皮-表皮交界处，并位于邻近 这表明它们可能影响病毒的再激活。我们建议的研究将 评估这些HSV-2特异性CD 8 + T细胞在原位的持久性，并确定它们的排出是否是 与随后的病毒再激活有关。HSV特异性CD 4+和CD 8 + T细胞在体内发生了改变 功能简介具体目标3将是使用多参数流式细胞术来表征这些 功能缺陷上述研究将提供新的信息，HSV特异性的作用， CD 8 + T细胞应答在OI的粘膜再活化中起作用，并提供了提供新的治疗方法的潜力。 疾病管理的治疗方法。