Mucosal Chemokines and Inflammation in SIV Transmission and Pathogenesis

SIV 传播和发病机制中的粘膜趋化因子和炎症

• 批准号: 8724017
• 负责人: Phalguni GUPTA
• 金额: $ 70.45万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8724017
• 关键词: Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Binding; Biology; CCL20 gene; CCL23 gene; CCL25 gene; CCR5 gene; CCR9 gene; CD4 Positive T Lymphocytes; Cells; Chronic; Dendritic Cells; Disease; Drug or chemical Tissue Distribution; Elements; Environment; G-Protein-Coupled Receptors; GPR2 gene; Gastrointestinal tract structure; Genetic Transcription; HIV; HIV-1; Helper-Inducer T-Lymphocyte; Homing; Immune; Immune system; Infection; Inflammation; Inflammatory; Intestines; Large Intestine; Link; Lymphatic; Lymphocyte; Lymphoid; Lymphoid Tissue; Macaca; MicroRNAs; Molecular Profiling; Mucosal Immunity; Mucositis; Mucous Membrane; Pathogenesis; Pathologic; Play; Positioning Attribute; Process; Property; Proteins; Recruitment Activity; Role; SIV; Sexual Transmission; Signal Transduction; Signaling Protein; Small Intestines; Surface; Tissues; Transcriptional Regulation; Viral; Virus; antimicrobial; cell motility; cell type; chemokine; combat; improved; in vivo; microbiome; neutralizing monoclonal antibodies; next generation sequencing; novel; promoter; rectal; reproductive; simian virus; success; tool; trafficking; transmission process

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.

描述：粘膜表面在 HIV-1 的传播和发病机制中发挥多种作用。 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，肠道组织是 CD4+ T 辅助细胞早期和持续损失的关键区室。与所有淋巴组织一样，胃肠道 (GI) 具有高度动态性，免疫细胞在组织实质中进出。细胞的这种运动很大程度上是由趋化因子驱动的。作为粘膜免疫系统的重要组成部分，趋化因子在HIV-1和相关猿猴病毒SIV的传播以及随后的发病机制中发挥着多种直接和间接的作用。我们将在此提出的研究中探讨趋化因子和炎症在 SIV 传播和病毒复制控制中的作用，并准备好进行干预以增强或中和体内粘膜趋化因子。关于 SIV 的传播，CCL20 与促进 SIV 粘膜传播的炎症环境有关，与其促炎特性一致。 CCL20 还具有直接抗 HIV 特性并刺激病毒限制因子 APOBEC3G。此外，它是粘膜 Th17 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 传播和发病机制中粘膜表达的趋化因子子集，重点关注 CCL20。我们独特地准备了中和 CCL20 的猿化单克隆抗体，并深入了解趋化因子的表达和功能，以确定 CCL20 和其他趋化因子在 SIV 传播和发病机制中所发挥的作用。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 CCL20 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影响，明确抗趋化因子治疗的作用机制； (3) 确定 CCL20 生物学的新功能和表达控制方面。