SAFETY AND EFFICACY OF SHIV VACCINE IN MACAQUES

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。这笔赠款支持两种类型的研究。首先，研究了猕猴SHIVKU感染的神经发病机制。这是一种X4病毒，在感染的病毒期入侵大脑，并保持休眠，直到动物由于病毒在CD4T淋巴细胞中的高效复制而产生免疫抑制。大脑中高效的病毒复制仅限于巨噬细胞，神经病理变化与趋化因子CXCL10和IL-4的表达有关，CXCL10对神经元有毒性，IL-4促进巨噬细胞中的病毒复制。其次，对活疫苗效力的持续研究表明，活疫苗诱导的免疫取决于疫苗病毒的持久性，并且在病毒被消除后，动物变得容易受到致病挑战病毒的致命疾病的影响。这种活病毒显然未能诱导记忆免疫反应。用活疫苗再次免疫可延长活疫苗的保护期。这重新建立了持续感染和伴随的保护性免疫。持续感染的特点是潜伏感染，只有用抗CD8淋巴细胞的抗体免疫动物才能重新激活病毒复制。随着CD8细胞计数的恢复，疫苗病毒的复制再次受到抑制

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. Two types of studies were supported in this grant. First, studies were directed to mechanisms regulating neuropathogenesis of SHIVKU infection in macaques. This is an X4 virus that invades the brain during the viremic phase of infection and remains dormant until the animal becomes immunosuppressed as a result of the highly productive replication of the virus in CD4 T lymphocytes. Productive virus replication in the brain was confined to macrophages and neuropathological changes correlated with expression of the chemokine CXCL10 that was toxic to neurons and IL-4 that promoted virus replication in the macrophages. Second, continuation of studies on efficacy of a live vaccine showed that immunity induced by the live vaccine depended on persistence of the vaccine virus, and that following elimination of the virus, the animal became susceptible to fatal disease by pathogenic challenge viruses. The live virus apparently failed to induce memory immune responses. The duration of protection by the live vaccine could be extended by re-immunization with the live vaccine. This re-established the persistent infection and the concomitant protective immunity. The persistent infection was characterized by dormant infection and virus replication could only be reactivated by immunosuppression of the immunized animals with antibodies against CD8 lymphocytes. Following recovery of the CD8 cell count, replication of the vaccine virus was again suppressed