Induction of robust T cell response to RRV-LANA

诱导 T 细胞对 RRV-LANA 产生强烈反应

• 批准号: 8660772
• 负责人: SCOTT W WONG
• 金额: $ 22.84万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660772
• 关键词: Address; Animal Model; Animals; Antigens; B-Lymphocytes; Biological; Biopsy; Blood; Blood specimen; Bronchoalveolar Lavage; CD8B1 gene; Control Groups; Cytomegalovirus; Cytomegalovirus Vaccines; Development; Disease; Exhibits; Genome; HIV; HIV-1; Herpesviridae Infections; Human; Human Herpesvirus 8; Hyperplasia; Immune response; Immunity; Incidence; Individual; Infection; Integration Host Factors; Intravenous; Kaposi Sarcoma; Light; Lung; Lymphoproliferative Disorders; Macaca mulatta; Malignant Neoplasms; Modeling; Monitor; Non-Hodgkin' s Lymphoma; Organ Transplantation; Outcome; Pathogenesis; Patients; Peptides; Population; Property; Rhadinovirus; SIV; Syndrome; System; T cell response; T-Lymphocyte; Techniques; Testing; Tissue Banks; Tissue Sample; Tissues; Vaccinated; Vaccination; Vaccines; Viral Load result; Virus; Virus Diseases; acquired immunodeficiency; cohort; gamma-2 herpesvirus; immunogenicity; in vivo Model; latency-associated nuclear antigen; lymph nodes; mutant; nonhuman primate; novel vaccines; prevent; public health relevance; response; therapeutic vaccine; vaccine evaluation; vector

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.

描述：卡波西肉瘤是在艾滋病患者中观察到的主要癌症。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/所有方面的体内模型对于开发和测试新疫苗以预防KSHV感染和疾病的增加是绝对需要的。目前，猴免疫缺陷病毒（SIV）和恒河猴横纹肌病毒（RRV）实验感染的动物发生类似于合并KSHV的艾滋病患者的B细胞淋巴细胞增生性疾病（LPD），因此KSHV样疾病的恒河猴（RM）模型满足了这些方面的大部分要求。重要的是，RM对RRV感染表现出与人类感染KSHV相似的免疫反应。具体来说，感染RRV的RM具有较低的CD4+和CD8+ T细胞对病毒的反应，这可能是允许病毒维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巨细胞病毒（RhCMV）疫苗载体系统的特性，以刺激能够识别RRV潜伏期相关核抗原（LANA）的RM中强大的T细胞反应。一旦免疫动物对RRV LANA的免疫反应具有特征，将对这些动物进行RRV攻击，并监测病毒感染和持久性。本研究的长期目标是评估RhCMV载体诱导对RRV- lana产生强烈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。为解决这一问题，提出了以下特异性目的：特异性目的1:RhCMV US8-11-LANA在恒河猴中的免疫原性。特异性目的2：接种RhCMV us8 -11- lana疫苗的动物免受野生型RRV的攻击。