IMMUNOGENICITY STUDIES OF RABIES VIRUSES EXPRESSING HIV-1 OR SIV

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。狂犬病毒（RV）是一种横纹肌病毒家族的单链RNA病毒，最近被开发为HIV-1的新型候选疫苗。作为小鼠减毒活疫苗，RV已被证明能诱导对HIV-1 Env和Gag产生强烈和持久的免疫反应。此外，如果gp160细胞质尾结构域（CD）被RV G取代，单个RV糖蛋白(G)可以在功能上被HIV-1 Env取代。这些表达Env的替代病毒或G缺失（DG）病毒具有HIV-1样细胞性，因此靶向CD4+/HIV-1共受体阳性细胞。本报告描述了在恒河猴中表达Env的g缺失RV的安全性、复制能力和免疫原性的原理证明研究。结果表明，这些病毒能有效感染恒河猴外周血单个核细胞（PBMCs），并能使接种动物血清转化为RV核糖核酸颗粒（RNP）。用表达SHIV-89.6P包膜的g缺失病毒接种动物，在SHIV-89.6P攻毒后产生高滴度病毒中和抗体和env特异性细胞免疫应答。重要的是，没有证据表明CD4+ t细胞损失和血浆病毒载量在攻击后六周被控制到不可检测的水平。这只动物在挑战后的22周内一直保持健康，没有任何疾病迹象。

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.