SAFETY AND EFFICACY OF SHIV VACCINE IN MACAQUES

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。这项拨款支持两种类型的研究。首先，针对猕猴SHIVKU感染的神经发病机制进行了研究。这是一种X4病毒，在感染的病毒血症阶段侵入大脑，并保持休眠状态，直到动物的免疫抑制，这是由于病毒在CD4 T淋巴细胞中高效复制的结果。大脑中的病毒复制仅限于巨噬细胞，神经病理变化与趋化因子CXCL10的表达相关，CXCL10对神经元有毒，IL-4促进巨噬细胞中的病毒复制。第二，对活疫苗效力的持续研究表明，活疫苗诱导的免疫力取决于疫苗病毒的持久性，在病毒被消灭后，动物对致病性攻击病毒的致命疾病变得易感。活病毒显然不能诱导记忆免疫反应。通过再次接种活疫苗，可以延长活疫苗的保护时间。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，病毒复制只能通过免疫动物免疫抑制CD8淋巴细胞抗体才能被重新激活。CD8细胞计数恢复后，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