INFANT IMMUNOPROPHYLAXIS AGAINST A PRIMATE LENTIVIRUS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们构建了猴-人类免疫缺陷病毒(SHIV)的新毒株，这种病毒部分是猴子艾滋病病毒(称为SIV)，部分是人类艾滋病病毒(称为HIV-1)。其中之一，Shiv-Bo159N4，编码了一种原发HIV-1的包膜基因，该基因适用于人脑来源的细胞。SHIV-Bo159N4在所有受试猴子的血细胞中复制良好，并通过CCR5进入细胞，形成含有许多核的巨细胞。我们用这种新病毒通过静脉和粘膜接种恒河猴(RM)。为了增加病毒血症，CD8+细胞和B细胞在接种后不久就被耗尽；血浆和脑脊液中可见高水平的病毒RNA。我们还在CD8+细胞耗尽的情况下接种了辫子猴；再次在血浆和脑脊液中观察到高病毒载量。对脑脊液病毒RNA载量最高的动物实施安乐死，分离小胶质细胞并转移给新的受体。脑切片正在接受测试，以寻找生产性病毒感染和脑部疾病的证据。我们目前正在跟踪慢性感染的RM和辫子猴的疾病。 我们还构建了编码非洲甲型HIV-1毒株包膜基因的SHIV-KNH1144。SIV-KNH1144适应于RM，产生了大量的病毒库，正在进行分析。 接下来，我们展示了从HIV感染者分离的新型人类单抗(MAb)的被动免疫完全保护婴儿RM免受含有HIV C分支囊膜的中和敏感SIV的粘膜攻击。这是第一次证明中和单抗可以跨不同的分支进行保护。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have constructed new strains of simian-human immunodeficiency virus (SHIV), viruses that are part monkey AIDS virus (termed SIV), part human AIDS virus (termed HIV-1). One of these, SHIV-Bo159N4, encodes the envelope gene of a primary HIV-1 that was adapted in human brain-derived cells. SHIV-Bo159N4 replicated well in blood cells of all monkeys tested and enters cells via CCR5 and forms giant cells containing many nuclei. We inoculated rhesus monkeys (RM) intravenously and mucosally with this new virus. To increase viremia, CD8+ cells and B cells were depleted shortly after inoculation; high viral RNA levels were seen in plasma and cerebrospinal fluid (CSF). We also inoculated pigtailed monkeys under depletion of CD8+ cells; again, high viral loads were observed in plasma and CSF. Animals with the highest CSF viral RNA loads were euthanized, microglia were isolated and transferred to new recipients. Brain sections are being tested for evidence of productive viral infection and brain disease. We are currently following chronically infected RM and pigtailed monkeys for disease. We have also constructed SHIV-KNH1144, which encodes the envelope gene of an African clade A HIV-1 strain. SHIV-KNH1144 was adapted to RM, a large virus stock was generated and is undergoing analysis. Next, we showed that passive immunization with a novel human monoclonal antibody (mAb) isolated from an HIV-infected person completely protected infant RM against mucosal challenge with a neutralization-sensitive SHIV containing an HIV clade C envelope. This is the first demonstration that a neutralizing mAb can protect across different clades.