Preventing TB with intravenous BCG in SIV-infected macaques

项目摘要 由结核分枝杆菌（Mtb）引起的结核病（TB）是HIV+患者死亡的最常见原因。 个体虽然抗逆转录病毒和抗分枝杆菌药物已经减少了艾滋病毒+患者的结核病负担， 但是，它们并不能完全有效地应对这一全球健康负担。唯一可用的结核病疫苗是 婴儿皮内注射的减毒活分枝杆菌卡介苗（BCG）。而 这为儿童期预防非肺结核提供了实质性保护，但对肺结核几乎没有影响 成人的价格。然而，我们最近已经表明，静脉注射卡介苗（BCG IV）可显著提高 保护SIV阴性猕猴免受结核病感染。 博士Scanga在他的HIV/Mtb合并感染的猕猴模型中进行了BCG IV的初步研究。动物 感染致病性SIV几个月，然后与强毒Mtb共感染， 严重的结核病比类似感染SIV的未感染动物。在他们的初步研究中，SIV+猕猴的接种 BCG IV诱导的免疫力与SIV未感染恒河猴的免疫力相似， 在6/7只动物中感染结核病。此外，没有传播BCG的迹象。这一前所未有 SIV+动物的结核病保护提供了令人兴奋的证据，即BCG IV可以是安全的，免疫原性的， 在慢性SIV感染的NHP中， 虽然这些数据是挑衅性的，但关于BCG IV提供的机制仍有很多需要了解的地方。 如此惊人的保护。在本R 01提案中，我们将扩展这些令人兴奋的结果，以完善BCG的能力 IV保护SIV+猕猴免受Mtb感染。最重要的是，我们将全面 免疫学方法，包括偏倚和无偏倚，以确定免疫相关性和机制 在预先存在SIV的情况下，BCG IV介导的抗结核保护作用。这将证明， 可能确实有可能保护艾滋病毒感染者免受结核病的感染，并将指导结核病的发展。 可以保护这些高度脆弱人群的疫苗方法。 我们组建的团队包括结核病、疫苗和尖端技术领域的专家 这将使我们更好地理解卡介苗IV对SIV+动物的显著保护作用。我们已经有 建立合作关系，并确保成功完成这项非常令人兴奋的研究。

PROJECT SUMMARY Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is the most common cause of mortality in HIV+ individuals. Although antiretroviral and antimycobacterial drugs have reduced the burden of TB in the HIV+ population, they are incompletely effective against this global health burden. The only available TB vaccine is the live attenuated mycobacterium Bacillus Calmette-Guerin (BCG) that is given intradermally to infants. While this provides substantial protection against non-pulmonary TB in childhood, it has little impact on pulmonary TB rates in adults. However, we have shown recently that BCG delivered intravenously (BCG IV) conferred dramatic protection from TB in SIV-negative macaques. Dr. Scanga conducted a preliminary study of BCG IV in his macaque model of HIV/Mtb co-infection. Animals infected with pathogenic SIV for several months that were then co-infected with virulent Mtb exhibited more severe TB than did similarly-infected SIV-naïve animals. In their preliminary study, vaccination of SIV+ macaques with BCG IV induced immunity that parallels that seen in SIV-naïve rhesus and conferred dramatic protection from TB in 6/7 animals. Furthermore, there were no signs of disseminated BCG. This unprecedented protection from TB in SIV+ animals provides exciting evidence that BCG IV can be safe, immunogenic, and protective in NHP with chronic SIV infection While these data are provocative, there is still much to learn about the mechanisms by which BCG IV provides such striking protection. In this R01 proposal, we will extend these exciting results to refine the ability of BCG IV to protect SIV+ macaques from infection with Mtb. Most importantly, we will use comprehensive immunologic approaches, both biased and unbiased, to determine the immune correlates and mechanisms of BCG IV-mediated protection against TB in the context of pre-existing SIV. This will demonstrate that it may indeed be possible to protect persons infected with HIV from TB and will guide the development of TB vaccine approaches that can protect this highly vulnerable population. The team we have assembled includes experts in the field of TB, vaccines, and the cutting-edge technologies that will allow us to understand better the remarkable protection of SIV+ animals with BCG IV. We already have an established collaborative relationship and ensures successful completion of this very exciting study.