The Impact of Pre-exisiting SIV on Host Immunity to M tuberculosis in Macaques

 描述（由申请人提供）： 结核分枝杆菌（Mycobacterium tuberculosis，Mtb）感染超过10亿人，每年导致900万结核病（TB）病例，并且每年导致超过100万人死亡。大多数结核分枝杆菌感染者无法消除病原体，但可以控制它并建立潜伏性结核病。发展活动性结核病的最大风险因素之一是合并感染人类免疫缺陷病毒（HIV）。最近的研究表明，大多数合并感染者首先感染艾滋病毒，随后合并感染结核分枝杆菌。T细胞反应在遏制Mtb方面起着关键作用，因此免疫缺陷的HIV+个体可能发展为Mtb并不奇怪。 活动性肺结核值得注意的是，接受高效抗逆转录病毒疗法的艾滋病毒阳性者或CD 4计数高的人仍然比艾滋病毒初治者更有可能发展为活动性结核病。显然，除了血液中CD 4的简单消耗外，其他因素也会导致合并感染个体活动性结核病的可能性增加。感染结核分枝杆菌的非人灵长类动物再现了人类结核病的所有方面，而感染猿猴免疫缺陷病毒（SIV）的灵长类动物则表现出类似于HIV/AIDS的症状。使用SIV+猕猴（MCM），我们将确定预先存在的SIV感染干扰宿主控制结核分枝杆菌感染的机制。我们假设SIV损害肉芽肿中T细胞的早期Th 1和Th 17细胞因子应答，这阻止了Mtb复制的控制。为了验证这一假设，我们将用四聚体分子追踪SIV和Mtb共感染的MCM的血液和肉芽肿病变中的表位特异性T细胞。我们还将使用最先进的PET/CT成像来表征Mtb共感染后SIV+动物肺组织中肉芽肿的早期形成。最后，我们将确定一种新的亚单位结核病疫苗是否可以增强SIV+动物的细胞免疫应答，并重新建立控制随后Mtb攻击的能力。该提案汇集了两名具有互补专业知识的研究人员，为在既存艾滋病毒感染的情况下损害结核分枝杆菌感染控制的事件提供新的见解。在高度相关的动物模型中进行的新研究将有助于了解早期Mtb感染中防止潜伏性TB建立的关键事件，并将评估在SIV+动物中增强对Mtb免疫力的潜力。

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) infects over one billion people, resulting in 9 million cases of tuberculosis (TB) annually, and over 1 million deaths each year. The majority of Mtb-infected individuals are unable to eliminate the pathogen, but can control it and establish latent TB. One of the biggest risk factors for developing active TB is co-infection with human immunodeficiency virus (HIV). Recent studies have shown that the majority of co-infected individuals are infected with HIV first and subsequently co-infected with Mtb. T cell responses play a critical role in containing Mtb, so it is not surprising that immunodeficient HIV+ individuals are likely to develop active TB. Notably, HIV+ persons on HAART or who have high CD4 counts are still more likely to develop active TB than someone who is HIV-naïve. Clearly, factors besides simply CD4 depletion in blood must contribute to the increased likelihood of active TB in co-infected individuals. Nonhuman primates infected with Mtb recapitulate all aspects of human TB, and those infected with simian immunodeficiency virus (SIV) display symptoms similar to HIV/AIDS. Using SIV+ Mauritian cynomolgus macaques (MCM), we will identify the mechanism by which pre-existing SIV infection interferes with host control over an Mtb infection. We hypothesize that SIV impairs the early Th1 and Th17 cytokine response by T cells in granulomas, which prevents control of Mtb replication. To test this hypothesis, we will track epitope-specific T cells with tetrameric molecules in the blood and granuloma lesions of MCM co-infected with SIV and Mtb. We will also use state-of-the-art PET/CT imaging to characterize the early formation of granulomas in lung tissue of SIV+ animals after Mtb co-infection. Lastly, we will determine if a novel subunit TB vaccine can boost cellular immune responses in SIV+ animals and re- establish the ability to control a subsequent Mtb challenge. This proposal brings together two investigators with complimentary expertise to provide new insights into the events that impair control of Mtb infection in the setting of pre-existing HIV infection. Novel studies in a highly relevant animal model will lead to an understanding of the critical events in early Mtb infection that prevent establishment of latent TB and will evaluate the potential of boosting immunity to Mtb in SIV+ animals.