NEURODEGENERATION AND NEURORESTITUTION IN MURINE HIV-1 ENCEPHALITIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。一种有效的预防人类免疫缺陷病毒1型（HIV-1）感染的疫苗经过20年的紧张研究仍然难以捉摸。一项重大挑战是HIV-1对人类免疫细胞的高度限制性，这妨碍了在小动物模型系统中进行疫苗试验。这种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佳方法是将其施用于主要宿主，然后在感兴趣的人群中使用一系列病毒株进行挑战。其他人和我们实验室最近的工作表明，人类适应性免疫效应可以转移并在啮齿动物中发挥作用。这样的啮齿动物模型系统包含人类抗原呈递树突状细胞（DC）、T细胞和B细胞，并允许HIV-1感染。将人外周血淋巴细胞移植到非肥胖糖尿病严重联合免疫缺陷小鼠（PBL, hu-PBL-NOD/SCID）体内，可诱导人类HIV-1特异性细胞毒性T淋巴细胞，中和抗体反应，并提供抵抗病毒攻击的保护。我们将研究编码C亚型HIV-1包膜和Gag、Pol、Nef蛋白的HSV-1扩增子载体的免疫原性，通过评估它们在体外与DC的相互作用，以及转导DC在体内刺激体液和细胞免疫反应的能力。我们将检测选定的候选疫苗在用C和b亚型的几种主要病毒分离株在体内攻击dc疫苗接种的hu-PBL-NOD/SCID小鼠后控制病毒复制和保护CD4+T淋巴细胞的能力。这项工作将揭示C亚型疫苗的功效，探索保护的相关因素，并加快合理的免疫原选择过程，从而导致人类疫苗试验。

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.