KSHV REGULATION OF INNATE CYTOKINE RESPONSES AND T CELL ACTIVATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 背景 卡波西肉瘤相关疱疹病毒(KSHV)是卡波西肉瘤(KS)的病原体。现有数据表明，T细胞反应对控制KS的进展至关重要，而抗原提呈细胞(APC)为产生这些反应提供了重要的激活信号。目前尚不清楚APC感染KSHV是否会损害有效的T细胞反应，从而促进KS的进展。我们的模型系统显示，KSHV通过感染APC的多种KSHV编码机制损害T细胞的激活，包括改变APC产生的细胞因子。因此，我们建议使用这些系统，包括来自人类患者的原代细胞，来确定KSHV调节APC功能和T细胞激活的机制。 理理 KSHV是导致癌症的最常见原因，特别是在艾滋病毒感染患者中引起的口腔癌。口服KS对现有的治疗方法具有抵抗力，预示着一种不祥的预后。更好地了解KSHV是如何通过感染APC来调节T细胞激活的，可能为开发基于免疫或抗炎的治疗或预防口腔KS的策略提供新的机会。 研究设计和结果测量 利用人和小鼠的APC作为KSHV感染和细胞培养中基因转移的靶点，我们将首先鉴定参与免疫抑制分子APC分泌的KSHV编码的特定基因，包括IL-6、IL-10和反应氮物种(RNS)。接下来，利用抗原非依赖性和抗原依赖性T细胞活化试验，我们将测试减少KSHV感染的APC分泌IL-6、IL-10和RNS并恢复这种环境中T细胞激活的干预策略。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS). Existing data suggest that T cell responses are critical for the control of KS progression, and antigen-presenting cells (APC) provide important activation signals for generating these responses. Whether KSHV infection of APC impairs effective T cell responses thereby promoting KS progression is unknown. Our model systems show that KSHV impairs T cell activation through multiple KSHV-encoded mechanisms involving infection of APC, including alteration of cytokine production by APC. Therefore, we propose to use these systems, including primary cells from human patients, to identify mechanisms for KSHV regulation of APC function and T cell activation. Rationale KSHV is the most common cause of cancer, and specifically oral cancers, arising in HIV-infected patients. Oral KS is resistant to existing therapies and portends an ominous prognosis. A better understanding of how KSHV regulates T cell activation through the infection of APC may provide new opportunites for developing immune-based or anti-inflammatory strategies for the treatment or prevention of oral KS. Study design and outcome measures Using human and murine APC as targets of KSHV infection and gene transfer in cell culture, we will first identify specific KSHV-encoded genes involved in APC secretion of immunoinhibitory molecules, including IL-6, IL-10, and reactive nitrogen species (RNS). Next, using antigen-independent and antigen-dependent T cell activation assays, we will test interventional strategies for reducing IL-6, IL-10, and RNS secretion by KSHV-infected APC and restoring T cell activation in this environment.