IMMUNOGENICITY STUDIES OF RABIES VIRUSES EXPRESSING HIV-1 OR SIV

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。狂犬病病毒(RV)是横纹病毒家族的一种单链RNA病毒，最近被开发为HIV-1的新型候选疫苗。作为一种在小鼠体内的减毒活疫苗，RV已被证明能诱导对HIV-1Env和Gag的强烈和持久的免疫反应。此外，如果gp160胞浆尾部结构域(CD)被RV G所取代，那么单个RV糖蛋白(G)就可以被HIV-1 Env所取代。这些表达Env的代用或G缺失(DG)病毒具有类似HIV-1的细胞嗜性，因此靶向于CD4+/HIV-1共受体阳性细胞。本文对表达Env的G-缺失RV在恒河猴体内的安全性、复制能力和免疫原性进行了原理性研究。结果表明，这些病毒能有效地感染恒河猴外周血单核细胞(PBMCs)，并能使免疫动物血清转化为RV核糖核酸颗粒(RNP)。用表达SIV-89.6P外膜的G缺失病毒免疫的动物，在SIV-89.6P攻击后产生了高滴度的病毒中和抗体和环境特异性细胞免疫应答。重要的是，没有证据表明CD4+T细胞丢失，到挑战后六周，血浆病毒载量被控制到无法检测到的水平。直到挑战后的22周，这只动物一直保持健康，没有疾病的迹象。

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. Rabies virus (RV), a single-stranded RNA virus of the Rhabdovirus family, has recently been developed as a novel vaccine candidate for HIV-1. As a live-attenuated vaccine in mice, RV has been shown to induce vigorous and long lasting immune responses to both HIV-1 Env and Gag. Further, the single RV glycoprotein (G) can be functionally replaced by HIV-1 Env if the gp160 cytoplasmic tail domain (CD) is replaced by that of RV G. These surrogate, or G-deleted (DG), viruses expressing Env assume an HIV-1-like cell tropism and are therefore targeted to CD4+/HIV-1 co-receptor positive cells. This report describes a proof of principle study of the safety, replication capacity and immunogenicity of G-deleted RV expressing Env in rhesus macaques. The results show these viruses can productively infect rhesus peripheral blood mononuclear cells (PBMCs) and vaccinated animals seroconvert to the RV ribonucleic acid particle (RNP). An animal vaccinated with a G-deleted virus expressing the SHIV-89.6P envelope developed high titer virus neutralizing antibodies and Env-specific cellular immune responses post-challenge with SHIV-89.6P. Importantly, there was no evidence of CD4+ T-cell loss and plasma viral loads were controlled to undetectable levels by six weeks post-challenge. The animal has remained healthy with no signs of disease up to twenty-two weeks post-challenge.