Mucosal Immune Dysfunction after SIV Infection

描述(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感染导致免疫系统的严重功能障碍，特别是粘膜组织，最终导致获得性免疫缺陷综合征和死亡。在HIV感染期间，胃肠道(GI)的完整性受到损害，这使得微生物产物从GI管腔转移到循环中，这有助于免疫激活。免疫激活是艾滋病毒感染期间疾病进展的最强预测因素，其特点是免疫系统的几乎每一只手臂都出现了失调。虽然HIV感染后粘膜免疫功能障碍的许多方面已经被描述，但引发这些事件的确切事件，以及这些功能障碍的机制仍不清楚。为了开发更有效的治疗方法，旨在恢复HIV感染期间健康的粘膜免疫功能，需要对HIV感染期间的粘膜免疫有更全面的了解。因此，我们建议评估猕猴在急性猴免疫缺陷病毒(SIV)感染过程中粘膜免疫系统改变的动力学和机制。我们假设，重要的动态平衡粘膜免疫细胞的丧失是由于粘膜组织中SIV复制导致的促炎细胞增加的结果。我们将使用两种方法来解决这一问题-在第一个目标中，我们将评估在急性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。我们推测，SIV感染后炎症增加会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种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害、微生物易位和体内免疫激活来解决这一问题。这将有助于更好地了解SIV感染后粘膜免疫功能障碍之间的时间关联，从而深入了解每一事件的因果关系。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潜在机制来扩展目标I。我们假设，粘膜组织中炎症的增加是促炎症细胞增殖和/或归巢增加的结果，这会由于功能丧失和/或死亡而导致有助于粘膜动态平衡的细胞丧失。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，我们将使用体外研究来评估是否可以改变黏膜免疫细胞的功能，这是基于我们的假设，即SIV感染后致炎分子的增加破坏了粘膜组织的动态平衡免疫功能。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如何以及为什么发生变化，并为开发治疗艾滋病毒感染的新治疗策略提供洞察力。

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.