Mucosal Chemokines and Inflammation in SIV Transmission and Pathogenesis

描述：粘液表面在HIV-1的传播和发病机制中起着多种作用。HIV-1的传播主要发生在直肠和生殖道粘膜表面，已知局部微环境会影响传播的成功。此外，肠组织是关键的隔室，其中存在早期和持续的CD 4 + T辅助细胞损失。与所有淋巴组织一样，胃肠道（GI）是高度动态的，免疫细胞进出组织实质。细胞的这种运动在很大程度上是由趋化因子驱动的。趋化因子作为粘膜免疫系统的重要组成部分，在HIV-1和相关的猴病毒SIV的传播以及随后的发病机制中发挥多种直接和间接的作用。我们将在本文提出的研究中解决趋化因子和炎症在SIV传播和控制病毒复制中的作用，并且独特地准备进行干预以增加或中和体内粘膜趋化因子。关于SIV的传播，CCL 20与促进SIV粘膜传播的炎性环境有关，这与其促炎特性一致。CCL 20还具有直接抗HIV特性，并刺激病毒限制因子APOBEC 3G。此外，它是粘膜Th 17细胞的关键归巢信号，这些细胞在SIV感染期间丢失。在这些研究中，我们将探讨SIV传播和发病机制中的粘膜表达趋化因子亚群，重点是CCL 20。我们拥有独特的猴源化单克隆抗体，可以中和CCL 20，并深入了解趋化因子的表达和功能，以确定CCL 20和其他趋化因子在SIV传播和发病机制中的作用。我们的总体假设是，抑制趋化因子驱动的炎症将减少SIV的传播和发病机制。为了解决这一假设，我们的具体目标是：（1）确定CCL 20在SIV粘膜传播和病毒控制中的作用;（2）通过鉴定抗趋化因子治疗对猕猴组织的作用来确定其作用机制;（3）鉴定CCL 20生物学的新功能和表达控制方面。

DESCRIPTION: Mucosal surfaces play multiple roles in the transmission and pathogenesis of HIV-1. Transmission of HIV-1 occurs primarily across rectal and reproductive tract mucosal surfaces and the local microenvironment is known to affect the success of transmission. In addition, intestinal tissues are key compartments in which there is early and sustained loss of CD4+ T helper cells. As with all lymphoid tissues, the gastrointestinal (GI) tract is highly dynamic with immune cells trafficking in and out of the tissue parenchyma. This movement of cells is driven in large part by chemokines. As critical components of the mucosal immune system, chemokines play multiple direct and indirect roles in the transmission of HIV-1 and the related simian virus, SIV, as well as subsequent pathogenesis. We will address the roles of chemokines and inflammation in SIV transmission and control of viral replication in the studies proposed here and are uniquely poised to intervene to augment or neutralize mucosal chemokines in vivo. With regard to the transmission of SIV, CCL20 has been linked to inflammatory milieus that facilitate SIV mucosal transmission, consistent with its proinflammatory properties. CCL20 also has direct anti-HIV properties and stimulates the viral restriction factor APOBEC3G. Further it is a critical homing signal for mucosal Th17 cells, which are lost during SIV infection. In these studies we will explore the mucosally-expressed subset of chemokines in the transmission and pathogenesis of SIV, focusing on CCL20. We are uniquely poised with simianized mAb that neutralizes CCL20, and a depth of understanding of chemokine expression and function, to determine the role that CCL20 and other chemokines play in SIV transmission and pathogenesis. Our overall hypothesis is that inhibition of chemokine-driven inflammation will reduce SIV transmission and pathogenesis. To address this hypothesis, our Specific Aims are to: (1) Determine the role of CCL20 in SIV mucosal transmission and viral control; (2) Define the mechanisms of action of anti-chemokine therapy via identification of its effects on macaque tissues; and (3) Identify new functional and expression control aspects of CCL20 biology.