VACCINATION AGAINST INTRAPARTUM HIV-1 CLADE C TRANSMISSIONV- SUPPLEMENT

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 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 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。 我们正在使用恒河猴（RM）模型的艾滋病毒感染和艾滋病开发潜在的疫苗策略，对艾滋病毒C支（HIV-C），世界上最流行的亚型。 为了测试候选疫苗的有效性，我们已经开发了一系列的混合病毒，称为猿猴-人类免疫缺陷病毒（SHIVs），通过结合猴艾滋病病毒（称为猿猴免疫缺陷病毒（SIV））的遗传成分与包膜基因克隆直接从最近传播的HIV-C株分离赞比亚婴儿。然后使SHIV适应RM，并产生用于RM模型中的粘膜攻击的大病毒原液。 我们用重组SIV Gag-Pol颗粒、HIV-1达特和三聚体HIV-C gp 160接种RM，其诱导交叉中和抗体（nAb）和稳健的细胞免疫应答。用编码异源R5 HIV-C包膜（与gp 160免疫原的差异为22.1%）的SHIV进行5次低剂量粘膜攻击后，94%的对照组出现病毒血症，而三分之一的疫苗接种者保持无病毒。 在高剂量SHIV再激发后，所有对照RM都被感染，而一些疫苗接种者仍然存在病毒血症。 峰值病毒血症与细胞免疫（p <0.001）和交叉nAb滴度（p <0.001）呈负相关。 这些数据首次同时将细胞和体液免疫反应与保护程度联系起来。 我们还分析了这些动物中抗体反应的精细特异性，以确定能够在HIV毒株中诱导广泛交叉中和抗体的包膜的特定位点，这是新HIV疫苗的关键组成部分。

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 are using the rhesus macaque (RM) model of HIV infection and AIDS to develop potential vaccine strategies against HIV clade C (HIV-C), the world's most prevalent subtype. To test the efficacy of candidate vaccines, we have developed a series of hybrid viruses, termed simian-human immunodeficiency viruses (SHIVs), by combining genetic components of monkey AIDS virus (termed simian immunodeficiency virus (SIV)) with envelope genes cloned directly from recently transmitted HIV-C strains isolated from Zambian infants. SHIVs are then adapted to RM and large virus stocks are generated for mucosal challenges in the RM model. We vaccinated RM with recombinant SIV Gag-Pol particles, HIV-1 Tat and trimeric HIV-C gp160, which induced cross-neutralizing antibodies (nAbs) and robust cellular immune responses. After five low-dose mucosal challenges with a SHIV that encoded a heterologous R5 HIV-C envelope (22.1% divergence from the gp160 immunogen), 94% of controls became viremic, whereas one third of vaccinees remained virus-free. Upon high-dose SHIV rechallenge, all control RM became infected, whereas some vaccinees remained aviremic. Peak viremia was inversely correlated with both cellular immunity (p0.001) and cross-nAb titers (p0.001). These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time. We are also analyzing the fine-specificity of the antibody responses in these animals to identify specific sites of envelope able to induce broadly cross-neutralizing antibodies across HIV strains, a key component of new HIV vaccines.