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

• 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
• 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

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)与T细胞一起被认为是第一批被靶向的白细胞 黏膜暴露后的HIV和(Ii)被证明能有效地将病毒传播到CD4*T细胞：直接转移 捕获/内化病毒(未成熟和成熟DC)和新合成病毒(未成熟)的转移 分布式控制系统、数据中心)。SIV-猕猴模型是研究树突状细胞在艾滋病毒传播和传播中作用的宝贵工具 疾病的发展。DC-T细胞环境为SIV/HIV的传播提供了一个独特的利基环境 体外和体内，不同的DC和T细胞亚群影响病毒的生长水平。野生型(WRT) VS Ne/-有缺陷的病毒复制取决于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。猕猴体内ANEF感染提供了 对wt感染的保护，表明在没有/7ef的情况下，建立了更强的效应器免疫。 此外，HSV-2感染可能通过持续增加的 组织内HIV靶细胞的数量和DC免疫刺激能力的下调。但 这种情况的确切机制尚不清楚。在这项新的5年计划中，我们正在扩大我们目前的 更深入地研究这种生物学，以确定艾滋病毒传播的这些早期事件。这 将通过两个新的具体目标来实现。具体地说，我们假设HSV-2增强了DC驱动 通过最初增加高易感A4/J7‘^’‘CD4*T细胞的数量来感染HIV 感染的早期阶段，以及抑制整体有效免疫力(DC功能降低，增强 Tregs)。相反，通过Poly(IC)(一种合成dsRNA的类似物)激活DC可以关闭HIV/SIV复制。 我们认为，这可能是由于(至少部分)DC的“适当”激活导致了触发 与生俱来的重要(例如(APOBEC)和限制艾滋病毒/SIV传播的适应性反应。通过研究wt和wt 4rtef感染时，我们计划描述IDCs和T细胞(a4p7‘^CD4’‘T细胞和Treg)在粘膜中的作用 变速箱。我们认为，HSV-2对DC函数的下调将增强IDC-A4/J7‘^’T 细胞和IDC-Treg参与即使在ANEF感染，而聚(LC)将限制HIV/SIV(和HSV-2)的复制 并增强抗病毒免疫(增加DC激活，减少a4l3f‘^CD4*T细胞)。识别 病毒传播的分子要求以及与病毒一致的先天和适应性反应 控制将为新的拦截策略提供新的目标。