Induction of robust T cell response to RRV-LANA

描述：卡波西肉瘤是艾滋病患者中最常见的癌症。能够概括卡波西肉瘤相关疱疹病毒(KSHV)感染和疾病的大部分/所有方面的活体模型绝对需要开发和测试新的疫苗来防止KSHV感染和疾病的增加。目前，KSHV样病的恒河猴(RM)模型可以满足这些方面的大部分要求，因为实验感染猴免疫缺陷病毒(SIV)和恒河猴狂犬病病毒(RRV)的动物会出现类似于共同感染KSHV的艾滋病患者的B细胞淋巴增殖性疾病(LPD)。重要的是，RM对RRV感染的免疫学反应与感染KSHV的人相似。具体地说，感染RRV的RM对病毒具有低的CD4+和CD8+T细胞反应，这可能是使病毒保持持续感染的一个宿主因素。在这项应用中，我们打算测试新开发的恒河猴巨细胞病毒(RhCMV)疫苗载体系统的特性，以刺激RM中能够识别RRV潜伏期相关核抗原(LANA)的强大T细胞反应。一旦接种RRV的动物对RRV LANA的免疫反应特征明确，这些动物就会受到RRV的攻击，并监测病毒的感染和持久性。本研究的长期目标是评估RhCMV载体诱导对RRV-LANA的强烈T细胞应答的能力，以及这种T细胞免疫是否能够清除RRV感染并在相关的KSHV感染模型中持续存在。为了解决这一问题，提出了以下特定目标：特定目标1：RhCMV US8-11-LANA在恒河猴中的免疫原性。具体目的2：保护免疫动物免受野生型RRV的攻击。

DESCRIPTION: Kaposi's sarcoma is the leading cancer observed in individuals with AIDS. In vivo models that can recapitulate most/all aspects of Kaposi's sarcoma-associated herpesvirus (KSHV) infection and disease are absolutely required to develop and test new vaccines to prevent the increase in KSHV infection and disease. Currently, the rhesus macaque (RM) model of KSHV-like disease fulfills most of these aspects, as animals experimentally infected with the simian immunodeficiency virus (SIV) and rhesus macaque rhadinovirus (RRV) develop B cell lymphoproliferative diseases (LPD) similar to AIDS patients co-infected with KSHV. Importantly, RM exhibit similar immunological responses to RRV infection, as humans infected with KSHV. Specifically, RM infected with RRV possess low CD4+ and CD8+ T cell responses to the virus, which could be one host factor that allows the virus to maintain a persistent infection. In this application, we intend to test the properties of the newly developed rhesus cytomegalovirus (RhCMV) vaccine vector system to stimulate a robust T cell response in RM that can recognize RRV latency-associated nuclear antigen (LANA). Once the immune responses to RRV LANA are characterized in vaccinated animals, the animals will be challenged with RRV and monitored for virus infection and persistence. The long-term objectives of this study aim to evaluate the ability of RhCMV vectors to induce a strong T cell response to RRV-LANA and whether this T cell immunity is capable of clearing RRV infection and persistence in a relevant model of KSHV infection. To address this, the following Specific Aims are proposed: Specific Aim 1: Immunogenicity of RhCMV US8-11-LANA in rhesus macaques. Specific Aim 2: Protection of RhCMV US8-11-LANA-vaccinated animals against challenge with wild type RRV.