VACCINATION AGAINST INTRAPARTUM HIV-1 CLADE C TRANSMISSIONV- SUPPLEMENT

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。 我们正在使用恒河猴(RM)艾滋病毒感染和艾滋病的模型来开发针对艾滋病毒C分支(HIV-C)的潜在疫苗策略，HIV-C是世界上最流行的亚型。为了测试候选疫苗的有效性，我们通过将猴子艾滋病病毒(称为猿猴免疫缺陷病毒(SIV))的基因成分与直接从最近从赞比亚婴儿分离的HIV-C毒株中克隆的包膜基因相结合，开发了一系列杂交病毒，称为猿人免疫缺陷病毒(SHIV)。然后，SHIV适应RM，并在RM模型中为粘膜挑战生成大量病毒库。 我们用重组SIV Gag-Pol颗粒、HIV-1 Tat和三聚体HIV-C gp160免疫RM，它们能诱导交叉中和抗体(NAB)和强大的细胞免疫反应。在用编码异源R5HIV-C包膜的SIV病毒(与gp160免疫原有22.1%的差异)进行5次低剂量粘膜攻击后，94%的对照组变成了病毒携带者，而三分之一的疫苗接种者仍然没有病毒。在大剂量SHV再次攻击时，所有对照RM都被感染，而一些疫苗接种者仍然是无反应的。病毒血症峰值与细胞免疫(p0.001)和交叉NAB滴度(p0.001)呈负相关。这些数据首次同时将细胞免疫反应和体液免疫反应与保护程度联系起来。 我们还在分析这些动物中抗体反应的细微特异性，以确定能够在艾滋病毒株之间诱导广泛交叉中和抗体的包膜的特定部位，这是新的艾滋病毒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.