Immune Responses to VSV/HIV/SIV Hybrids in Macaques

描述(由申请人提供)：传统上，活病毒疫苗提供了对病毒感染最有效的保护。这类疫苗由于在较长时间内高水平的细胞内合成抗原而诱导强烈的细胞和体液免疫反应。水疱性口炎减毒活病毒(VSV)载体表达其他病毒的蛋白，是动物模型中高效的疫苗。表达HIV-1Env和SIV Gag蛋白的VSV载体在恒河猴模型中被证明在预防艾滋病方面是有效的。用于猕猴的第一代VSV载体从VSV基因组的下游位置表达了Shiv、Gag和env基因。虽然这些载体表达了大量的SHIV蛋白，但现在已经开发出新的载体，允许从VSV基因组第一位置的表达位置进行更大的蛋白质表达。从第一个位置表达的蛋白质是感染细胞产生的主要蛋白质。该项目的主要目标是测试这些新载体在恒河猴体内的有效性，并包括表达Pol蛋白，以产生对其他CTL表位的免疫反应。免疫反应的大小将被定量跟踪，并与以前的研究进行比较，保护免受攻击的程度将通过分析峰值病毒载量、CD4T细胞计数、病毒载量设定点和对艾滋病的保护来监测。优化的VSV载体表达系统还将用于第二项研究，以确定基于VSV的疫苗系统是否也可以在使用SIV而不是SHIV89.6P的挑战中预防艾滋病。后面的一系列实验很重要，因为猕猴的SIV感染更接近于人类感染艾滋病毒。拟议的研究还将继续对7只感染希沃克病毒的、受疫苗保护的猕猴从最初的拨款期间进行跟踪，以确定疫苗保护的持久性。

DESCRIPTION (provided by applicant): Live viral vaccines have traditionally offered the most effective protection against viral infections. Such vaccines induce strong cellular and humoral immune responses due to high level intracellular synthesis of antigens over extended periods. Live attenuated vesicular stomatitis virus (VSV) vectors expressing proteins of other viruses are highly effective vaccines in animal models. VSV vectors expressing HIV-1 Env and SIV Gag proteins have proven effective in protecting against AIDS in a rhesus macaque model. The first generation of VSV vectors used in macaques expressed SHIV gag and env genes from a downstream position in the VSV genome. Although these vectors expressed substantial amounts of SHIV proteins, new vectors have now been developed that allow even greater protein expression from an expression site in the first position in the VSV genome. Proteins expressed from the first position are the major proteins produced in infected cells. The major goal of this project is to test the effectiveness of these new vectors in rhesus macaques and to include expression of Pol protein to generate immune responses to additional CTL epitopes. The magnitude of the immune responses will be followed quantitatively and compared with previous studies, and the extent of protection from challenge will be monitored through analysis of peak viral loads, CD4 T cell counts, viral load set points, and protection from AIDS. The optimized VSV vector expression system will also be used in a second study to determine if the VSV-based vaccine system can also protect from AIDS in a challenge using SIV rather than SHIV89.6p. This later series of experiments is important because SIV infection of macaques more closely mimics HIV infection in humans. The proposed studies will also continue the follow up on the seven SHIV-infected, vaccine-protected macaques from the initial grant period to determine durability of vaccine protection.