INFANT IMMUNOPROPHYLAXIS AGAINST A PRIMATE LENTIVIRUS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们已经构建了猴-人免疫缺陷病毒（SHIV）的新毒株，该病毒部分是猴艾滋病病毒（称为SIV），部分是人艾滋病病毒（称为HIV-1）。 其中之一，SHIV-Bo 159 N4，编码原代HIV-1的包膜基因，该基因适应于人脑来源的细胞。 SHIV-Bo 159 N4在所有受试猴的血细胞中复制良好，并通过CCR 5进入细胞，形成含有许多核的巨细胞。 我们用这种新病毒静脉和粘膜接种恒河猴（RM）。 为了增加病毒血症，在接种后不久耗尽CD 8+细胞和B细胞;在血浆和脑脊液（CSF）中观察到高病毒RNA水平。 我们还在CD 8+细胞耗竭的情况下接种猪尾猴;再次在血浆和CSF中观察到高病毒载量。 对具有最高CSF病毒RNA载量的动物实施安乐死，分离小胶质细胞并转移至新的受体。大脑切片正在进行测试，以寻找生产性病毒感染和大脑疾病的证据。 我们目前正在跟踪慢性感染的RM和猪尾猴的疾病。 我们还构建了SHIV-KNH 1144，它编码非洲进化枝A HIV-1株的包膜基因。 SHIV-KNH 1144已适应RM，生成了大量病毒库并正在进行分析。 接下来，我们表明，被动免疫与一种新的人单克隆抗体（mAb）分离的HIV感染者完全保护婴儿RM对粘膜的挑战与中和敏感的SHIV含有HIV C支包膜。 这是第一次证明中和mAb可以保护不同的进化枝。

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.