NEURODEGENERATION AND NEURORESTITUTION IN MURINE HIV-1 ENCEPHALITIS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。经过20年的紧张研究活动，人类免疫缺陷病毒1型(HIV-1)感染的有效预防性疫苗仍然难以找到。一个重大挑战是艾滋病毒-1对人类免疫细胞的高度限制性，这排除了在小动物模型系统中进行疫苗测试的可能性。这样的动物模型将概括人类接种疫苗后发生的适应性免疫反应。测试候选疫苗效力的最好方法是通过向主要宿主注射疫苗，其次是挑战感兴趣人群中存在的一系列病毒毒株。最近来自其他人和我们实验室的工作表明，人类适应性免疫的效应器可以在啮齿动物身上转移并发挥作用。这种啮齿动物模型系统包含人类抗原提呈树突状细胞(DC)、T和B细胞，并允许感染HIV-1。将人外周血淋巴细胞移植到非肥胖型糖尿病重症联合免疫缺陷小鼠(PBL，Hu-PBL-NOD/SCID)体内，可诱导出人类HIV-1特异性细胞毒T淋巴细胞，中和抗体反应，并对病毒攻击产生保护作用。我们将研究编码HIV-1C亚型包膜和Gag、Pol、Nef蛋白的HSV-1扩增载体在体外与DC的相互作用，以及转导的DC在体内刺激体液和细胞免疫应答的能力。我们将在DC免疫的Hu-PBL-NOD/SCID小鼠体内用C和B亚型的几个主要病毒分离株进行体内攻击后，检查选定的候选疫苗控制病毒复制和保存CD4+T淋巴细胞的能力。这些工作将揭示C亚型疫苗的有效性，探索保护相关因素，并加快导致人类疫苗测试的合理免疫原选择的进程。

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. An effective preventive vaccine for human immunodeficiency virus type 1 (HIV-1) infection remains elusive after 20 years of intense research activities. One significant challenge is the highly restricted nature of HIV-1 for human immune cells, which has precluded vaccine testing in small animal model systems. Such animal models would recapitulate adaptive immune responses as they occur following vaccination in humans. The best means to test candidate vaccine efficacy is through its administration to the primary host, followed by challenges with a spectrum of viral strains present in a population of interest. Recent work from others and our laboratory demonstrated that human effectors of adaptive immunity can be transferred and are functional in rodents. Such a rodent model system contains human antigen presenting dendritic cells (DC), T and B cells, and permits infection by HIV-1. Human peripheral blood lymphocytes transplanted into nonobese diabetic severe combined immunodeficient mice (PBL, hu-PBL-NOD/SCID) can elicit human HIV-1 specific cytotoxic T lymphocytes, neutralizing antibody responses and provide protection against viral challenge. We will investigate HSV-1 amplicon vectors encoding subtype C HIV-1 envelope and Gag, Pol, Nef proteins for immunogenicity by assessing their interaction with DC in vitro, and the ability of transduced DC to stimulate humoral and cellular immune responses in vivo. We will examine selected vaccine candidates for the ability to control viral replication and preserve CD4+T lymphocytes after in vivo challenge of DC-vaccinated hu-PBL-NOD/SCID mice with several primary viral isolates from subtypes C and B. Such work will uncover efficacy of subtype C vaccine, explore correlates of protection and speed the process of rational immunogen selection leading to human vaccine testing.