NEURODEGENERATION AND NEURORESTITUTION IN MURINE HIV-1 ENCEPHALITIS

小鼠 HIV-1 脑炎的神经变性和神经恢复

• 批准号: 7381203
• 负责人: LARISA Y POLUEKTOVA
• 金额: $ 30.22万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381203
• 关键词: NEURODEGENERATION; NEURORESTITUTION; MURINE; HIV; ENCEPHALITIS

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。经过20年的紧张研究活动，仍然没有找到一种有效的预防1型人类免疫缺陷病毒（HIV-1）感染的疫苗。一个重大挑战是HIV-1对人类免疫细胞的高度限制性，这使得无法在小动物模型系统中进行疫苗测试。这样的动物模型将重现人类接种疫苗后发生的适应性免疫应答。测试候选疫苗有效性的最佳方法是通过将其施用于主要宿主，然后用感兴趣的群体中存在的一系列病毒株进行攻击。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物可以转移，并在啮齿动物中发挥作用。这种啮齿动物模型系统含有人抗原呈递树突细胞（DC）、T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型糖尿病重症联合免疫缺陷小鼠（PBL，hu-PBL-NOD/SCID）体内，可诱导人HIV-1特异性细胞毒性T淋巴细胞（CTL）产生中和抗体，并对病毒攻击提供保护。我们将研究HSV-1扩增子载体编码亚型C HIV-1包膜和Gag，Pol，Nef蛋白的免疫原性，通过评估它们与DC在体外的相互作用，以及转导的DC在体内刺激体液和细胞免疫应答的能力。我们将检查选定的候选疫苗在用来自亚型C和B的几种主要病毒分离株对DC接种的hu-PBL-NOD/SCID小鼠进行体内攻击后控制病毒复制和保护CD 4 +T淋巴细胞的能力。这些工作将揭示C亚型疫苗的有效性，探索保护的相关性，并加速导致人类疫苗测试的合理免疫原选择的过程。