Modulating mucosal DCs and T cells to limit SIV spread

树突状细胞（DC）已经（i）与T细胞一起沿着被认为是由T细胞靶向的第一批白细胞之一。 粘膜暴露后的HIV和（ii）显示出有效地将病毒传播到CD 4 * T细胞： 捕获/内化的病毒（未成熟和成熟DC）和转移新合成的病毒（未成熟 DC、iDC）。SIV-猕猴模型是研究DC在HIV传播中的作用的宝贵工具， 疾病进展。DC-T细胞环境提供了一个独特的小生境，SIV/HIV可以在其中繁殖。 体外和体内，不同的DC和T细胞亚群影响病毒生长水平。野生型（WRT） vs nef缺陷型（Anef）病毒复制依赖于DC的激活状态：wt克服了DC的激活。 IDC在DC-T细胞环境中促进感染的局限性。猕猴的体内Anef感染提供了 针对WT感染的保护，这表明在没有β EF的情况下，获得了更强的效应免疫。 此外，HSV-2感染可能通过持续增加HIV-1感染而增加HIV-1的传播。 组织内HIV靶细胞的数量和DC免疫刺激能力的下调。但 其确切机制尚不清楚。在这个新的5年计划中，我们正在扩大我们目前的 研究更深入地研究这种生物学，以确定艾滋病毒传播的早期事件。这 将通过两个新的具体目标来实现。具体来说，我们假设HSV-2增强了DC驱动的 HIV感染通过最初增加高敏感性a4/J7“^"^”CD 4 * T细胞的数量来实现。 感染的最早阶段，以及抑制整体有效免疫（DC功能降低， Tennis）。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（至少部分）DC的“适当”激活导致触发 重要的先天（例如，APOBEC）和限制HIV/SIV传播的适应性反应。通过研究WT和 我们计划描述iDC和T细胞（a4 p7 + CD 4 + T细胞和T细胞）在粘膜感染中的作用。 传输我们提出HSV-2对DC功能的下调将增强iDC-a4/J7“”^“T 细胞和IDC-Treg参与，即使在Anef感染，而聚（IC）将限制HIV/SIV（和HSV-2）的复制 并增强抗病毒免疫力（增加的DC活化，更少的α 4/3 β-CD 4 + T细胞）。识别 病毒传播的分子要求以及与病毒相符的先天和适应性反应 控制将为新的阻断策略提供新的靶点。

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.