Modulating mucosal DCs and T cells to limit SIV spread

调节粘膜 DC 和 T 细胞以限制 SIV 传播

基本信息

批准号：
8702072
负责人：
Nina R. Derby
金额：
$ 90.71万
依托单位：
POPULATION COUNCIL
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8702072
关键词：
Acute Antiviral Response Arts Attenuated Biology Blood CCR5 gene CD4 Positive T Lymphocytes Cell physiology Cells Clinical Coculture Techniques Data Dendritic Cells Dendritic cell activation Disease Progression Double-Stranded RNA Environment Event Flow Cytometry Fostering Functional disorder Growth HIV HIV Envelope Protein gp120 HIV Infections Human Herpesvirus 2 Immune Immunity In Vitro Infection Infection Control Instruction Interferons Leukocytes Macaca Measures Mediating Methods Microscopy Modeling Molecular Mucous Membrane Natural Immunity Population Predisposition Recruitment Activity Regulatory T-Lymphocyte Research Role SIV Sexual Transmission Signal Pathway Simplexvirus Site Staging System T-Lymphocyte Testing Time Tissues Viral Virus Virus Diseases Virus Replication Work adaptive immunity analog base cellular targeting chemokine cytokine immune activation immune function in vivo inhibitor/antagonist lymph nodes novel pathogen prevent protective effect rectal response tool transcription factor transmission process

项目摘要

Dendritic cells (DCs) have been (i) implicated, along with T cells, as one of the first leukocytes targeted by HIV after mucosal exposure and (ii) shown to transmit virus efficiently to CD4* T cells: direct transfer of captured/internalized virus (immature and mature DCs) and transfer of newly synthesized virus (immature DCs, iDCs). The SIV-macaque model is a precious tool to study the role of DCs in HIV transmission and disease progression. The DC-T cell milieu provides a distinctive niche in which SIV/HIV can propagate in vitro and in vivo, with different subsets of DCs and T cells influencing the level of virus growth. Wild type (wrt) vs ne/-defective {Anef) virus replication is dependent on the state of activation of the DC: wt overcomes the limitations of IDCs to foster infection in the DC-T cell milieu. In vivo Anef infection of macaques affords protection against wt infection, suggesting that in the absence of /7ef stronger effector immunity is mounted. In addition, HSV-2 infection augments HIV transmission possibly through the persistence of increased numbers of HIV target cells within the tissues and down-modulation of DC immunostimulatory capacity. But the exact mechanisms of such remain unclear. Within this new 5-year proposal we are expanding our current research to delve more deeply into this biology in order to define these early events in HIV transmission. This will be achieved through two new Specific Aims. Specifically, we hypothesize that HSV-2 enhances DCdriven HIV infection by initially increasing the numbers of highly susceptible a4/J7'^'^''CD4* T cells in the earliest stages of infection, as well as dampening overall effective immunity (reduced DC function, increased Tregs). Conversely, DC activation via poly(IC) (a synthetic analog of dsRNA) shuts down HIV/SIV replication. We believe that this might be due (at least in part) to the "proper" activation of DCs resulting in the triggering of important innate (e.g.. APOBEC) and adaptive responses that limit HIV/SIV spread. By studying wt and 4rtef infections we plan to delineate the role of iDCs and T cells (a4p7'^'^'^CD4'' T cells and Tregs) in mucosal transmission. We propose that the down-modulation of DC function by HSV-2 will enhance iDC-a4/J7'"^'' T cell and IDC-Treg involvement even in Anef infection, while poly(lC) wilt limit HIV/SIV (and HSV-2) replication and augment anti-viral immunity (increased DC activation, fewer a4l3f'^'^CD4* T cells). Identifying the molecular requirements for virus transmission and the innate and adaptive responses that coincide with virus control will provide new targets for novel blocking strategies.

树突状细胞（DC）已与T细胞一起被（i）与T细胞一起作为最早针对的白细胞之一粘膜暴露后的HIV和（ii）有效地将病毒传播到CD4* T细胞：直接转移捕获/内部的病毒（未成熟和成熟的DC）和新合成病毒的转移（未成熟 DC，IDC）。 SIV-Macaque模型是研究DC在HIV传播中的作用的宝贵工具疾病进展。 DC-T细胞环境提供了独特的利基市场，其中SIV/HIV可以在其中传播体外和体内，具有不同的DC和T细胞子集影响病毒生长水平。野生型（WRT） vs ne/-Defective {anef）病毒复制取决于DC的激活状态：WT克服了 IDC在DC-T细胞环境中促进感染的局限性。猕猴的体内牛脉感染防止WT感染的保护，表明在没有 /7ef的情况下，更强的效应子免疫已安装。此外，HSV-2感染可能通过持续增加而增加了HIV的传播组织内的HIV靶细胞数量和直流免疫刺激能力的下调。但这种确切机制尚不清楚。在这个新的5年建议中，我们正在扩大我们的当前为了定义艾滋病毒传播中的这些早期事件，研究更深入地研究了这种生物学。这将通过两个新的特定目标来实现。具体而言，我们假设HSV-2增强了DCDRIND HIV感染最初增加了高度易感的A4/J7'^'^''CD4* T细胞的数量最早的感染阶段以及抑制整体有效免疫（DC功能降低，增加 Tregs）。相反，通过poly（iC）（DSRNA的合成类似物）激活DC会关闭HIV/SIV复制。我们认为，这可能是由于DC的“适当”激活而导致触发的重要的先天（例如APOBEC）和限制HIV/SIV传播的自适应反应。通过研究WT和 4RTEF感染我们计划描绘粘膜中IDC和T细胞（A4P7'^'^'^CD4''T细胞和Tregs）的作用传播。我们建议HSV-2对DC功能的下调将增强IDC-A4/J7'^'t 细胞和IDC-Treg的参与即使参与贫血感染，而Poly（LC）Wilt Limit HIV/SIV（和HSV-2）复制和增强抗病毒免疫（增加DC激活，更少的A4L3F'^'^CD4* T细胞）。识别病毒传播以及与病毒一致的先天和自适应反应的分子需求控制将为新颖的阻塞策略提供新的目标。