Immune Responses to VSV/HIV/SIV Hybrids in Macaques

猕猴对 VSV/HIV/SIV 杂交种的免疫反应

• 批准号: 6711787
• 负责人: John K. Rose
• 金额: $ 62.32万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6711787
• 关键词: AIDS therapy; AIDS vaccines; HIV infections; Macaca mulatta; SDS polyacrylamide gel electrophoresis; Vesiculovirus; active immunization; antibody neutralization test; biotechnology; cell mediated lymphocytolysis test; cellular immunity; drug screening /evaluation; enzyme linked immunosorbent assay; flow cytometry; human immunodeficiency virus 1; humoral immunity; immunoprecipitation; inhalation drug administration; live vaccine; nonhuman therapy evaluation; polymerase chain reaction; recombinant virus; simian AIDSs; simian immunodeficiency virus; vaccine development; vector vaccine

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.

描述（由申请人提供）：活病毒疫苗传统上提供了最有效的预防病毒感染的保护。由于长时间的高水平细胞内抗原合成，此类疫苗诱导强烈的细胞和体液免疫应答。表达其他病毒蛋白的减毒水泡性口炎病毒（VSV）活载体在动物模型中是高度有效的疫苗。表达HIV-1 Env和SIV Gag蛋白的VSV载体已被证明在恒河猴模型中有效保护免受AIDS。用于猕猴的第一代VSV载体从VSV基因组的下游位置表达SHIV gag和env基因。尽管这些载体表达了大量的SHIV蛋白，但现在已经开发了新的载体，其允许从VSV基因组中第一位置的表达位点表达甚至更大的蛋白。从第一个位置表达的蛋白质是感染细胞中产生的主要蛋白质。该项目的主要目标是测试这些新载体在恒河猴中的有效性，并包括Pol蛋白的表达以产生对额外CTL表位的免疫应答。 将定量跟踪免疫应答的幅度，并与先前的研究进行比较，并通过分析峰值病毒载量、CD 4 T细胞计数、病毒载量设定点和艾滋病保护来监测对攻击的保护程度。优化的VSV载体表达系统也将用于第二项研究，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的攻击中保护免受AIDS。后面的一系列实验很重要，因为猕猴感染SIV更接近于人类感染HIV。拟议的研究还将从最初的资助期开始继续对七只感染SHIV、受疫苗保护的猕猴进行跟踪，以确定疫苗保护的持久性。