Mucosal Immune Dysfunction after SIV Infection

描述（由申请人提供）：目前，全球有超过3300万人感染了人类免疫缺陷病毒（HIV）。HIV感染导致免疫系统，特别是粘膜组织的大量功能障碍，最终导致获得性免疫缺陷综合征的进展和死亡。在HIV感染期间，胃肠道的完整性受到损害，这使得微生物产物从胃肠道的管腔转移到循环中，这有助于免疫激活。免疫激活是HIV感染期间疾病进展的最强预测因子，其特征是免疫系统几乎所有分支的失调。虽然已经描述了HIV感染后粘膜免疫功能障碍的许多方面，但导致这些事件的确切事件以及这些功能障碍背后的机制仍然不清楚。为了开发更有效的治疗方法，旨在恢复健康的粘膜免疫功能在HIV感染期间，需要更全面地了解粘膜免疫在HIV感染期间。因此，在这里，我们建议评估在急性猴免疫缺陷病毒（SIV）感染期间恒河猴粘膜免疫系统改变的动力学和机制。我们假设，由于SIV在粘膜组织中的复制，导致促炎细胞增加，从而导致必需稳态粘膜免疫细胞的丧失。我们将使用两种方法来解决这个问题——第一个目标是评估急性SIV感染期间胃肠道损伤和粘膜免疫功能障碍发生的动力学。我们假设SIV感染后炎症的增加导致体内平衡免疫细胞的丧失，进而导致胃肠道结构屏障的破坏。我们将通过评估体外多个粘膜免疫细胞的频率和功能，以及评估急性SIV感染期间多个时间点对胃肠道紧密上皮屏障的损伤、微生物易位和体内免疫激活来解决这个问题。这将有助于更好地理解SIV感染后粘膜免疫功能障碍之间的时间关联，从而深入了解每个事件的因果关系。在第二个目标中，我们将通过确定SIV感染后发生的粘膜功能障碍的机制来扩展目标1。我们假设粘膜组织中炎症的增加是促炎细胞增殖和/或归巢增加的结果，这导致由于功能丧失和/或死亡而导致有助于粘膜稳态的细胞的损失。为了解决这个问题，我们将评估这些细胞亚群的增殖、早期激活、凋亡、衰竭和归巢的标志物。此外，我们将利用体外研究来评估我们是否可以改变粘膜免疫细胞的功能，基于我们的假设，即SIV感染后促炎分子的增加会破坏粘膜组织的稳态免疫功能。综上所述，这些拟议的研究将深入评估SIV感染后粘膜免疫功能改变的方式和原因，并为开发治疗HIV感染的新治疗策略提供见解。

DESCRIPTION (provided by applicant): Currently, more than 33 million individuals are infected with human immunodeficiency virus (HIV) worldwide. HIV infection results in masive dysfunction of the immune system, particularly in mucosal tissues, which ultimately results in progression to Acquired Immunodeficiency Syndrome and death. During HIV infection, the integrity of the gastrointestinal (GI) tract is compromised, which allows microbial products to translocate from the lumen of the GI tract into circulation, which contributes to immune activation. Immune activation is the strongest predictor of disease progression during HIV infection, and is characterized by dysregulation of virtually every arm of the immune system. While many aspects of mucosal immune dysfunction after HIV infection have been described, the precise events which precipitate these events, and the mechanisms that underlie these dysfunctions are still unclear. In order to develop more effective therapeutic approaches aimed at restoring healthy mucosal immune function during HIV infection, a more complete understanding of mucosal immunity during HIV infection is needed. Thus, here we propose to evaluate both the kinetics and mechanisms by which the mucosal immune system is altered during acute Simian Immunodeficiency Virus (SIV) infection in rhesus macaques. We hypothesize that loss of essential homeostatic mucosal immune cells is the result of increased proinflammatory cells due to SIV replication in mucosal tissues. We will address this using two approaches- in the first aim, we will evaluate the kinetics by which damage to the GI tract and mucosal immune dysfunction occur during acute SIV infection. We hypothesize that increased inflammation after SIV infections results in loss of homeostatic immune cells, which in turn leads to damage to structural barrier of the GI tract. We will address this by evaluating the frequency and function of multiple mucosal immune cells ex vivo, and evaluating the damage to the tight epithelial barrier of the GI tract, microbial translocation and immune activation in vivo at multipe time points during acute SIV infection. This will allow a better understanding of temporal associations between dysfunctions in mucosal immunity after SIV infection to provide insight into cause and effect of each event. In the second aim, we will expand upon Aim I by determining the mechanisms underlying the mucosal dysfunctions that occur after SIV infection. We hypothesize that increased inflammation in mucosal tissues is the result of proliferation and/or increased homing of proinflammatory cells, and that this results in loss of cells that contribute to mucosal homeostasis due to loss in functionality and/or death. To address this, we will evaluate markers of proliferation, early activation, apoptosis, exhaustion, and homing of these cell subsets. Furthermore, we will use in vitro studies to assess whether we can alter the functions of mucosal immune cells based on our hypothesis that increased proinflammatory molecules after SIV infection abrogates homeostatic immune function in mucosal tissues. Taken together, these proposed studies will provide an in-depth assessment into how and why mucosal immune function is altered after SIV infection, and provide insight into developing novel therapeutic strategies for treatment of HIV infection. Public Health Relevance Statement (provided by the applicant): During HIV infection, there is massive dysfunction of the mucosal immune system that is associated with progression to AIDS, and the proposed studies are to determine the kinetics and mechanisms of this dysfunction after SIV infection. These studies will be essential to understand better how damage occurs in mucosal tissues during SIV infection in order to develop more effective therapeutic approaches aimed at treating HIV and AIDS.