Characterization of follicular dendritic cells as a reservoir for HIV

 产品说明：人类免疫缺陷病毒（HIV）是一种负链RNA病毒，感染人类CD 4 + T细胞，导致复制和细胞死亡。虽然感染是无法治愈的，但抗逆转录病毒治疗（ART）可以控制感染并部分恢复宿主的CD 4 + T细胞。尽管取得了成功，但病毒在淋巴结内仍以低水平存在，表明宿主储存库位于滤泡区域。更具体地说，病毒RNA不仅在CD 4 T细胞中被鉴定，而且在滤泡中被鉴定，并且与滤泡树突状细胞（FDC）显著共定位。如何 病毒是否被FDC在人体内长时间保留尚不清楚。FDC是基质来源的，并且它们是形成和维持B细胞滤泡以及募集CD 4 + T滤泡辅助细胞（TFH）（HIV的主要靶细胞）所必需的。最近，我们报道了FDC通过CD 21受体摄取免疫复合物，并周期性地将复合物循环到细胞表面。我们的中心假设是，HIV通过与免疫复合物相似的途径保留，并且感染性病毒周期性地循环到FDC表面，在那里它可以感染TFH。我们将在以下三个目标中检验这一假设：目标1。检验FDC（人和非人灵长类动物）通过CD 21内吞补体调理慢病毒并周期性循环病毒复合物至表面的假设。AIM 2.检验假设从感染个体中分离的FDC在体外将感染性病毒传播给CD 4 + T细胞， 可以用诱饵人CD 21受体阻断。AIM 3.测试可溶性人CD 21受体在非人灵长类动物中阻断FDC和幼稚B细胞对SIV滞留的功效。里程碑：第1年和第2年（R21时期）的重点是目标1和2。第一个重要的里程碑是确定从感染艾滋病毒的人中分离的FDC对艾滋病毒的保留。第二个重要的里程碑是发现用可溶性CD 21-IG融合蛋白治疗HIV感染的FDC在体外阻断病毒向未感染的人CD 4 T细胞的传播。第三个重要的里程碑是发现从SIV感染的非人灵长类动物中分离的FDC也保留病毒，并且用sCD 21-IG治疗阻断其向猴T细胞的传播。如果NIAID批准，目标3将作为赠款的R33部分启动3-5年。第四个重要的里程碑是证明了阻断C3 d-配体与FDC和B细胞上的CD 21受体的结合破坏了FDC在体内对SIV的滞留。

 DESCRIPTION: Human immune-deficiency virus (HIV) is a negative-stranded RNA virus that infects human CD4+ T cells leading to replication and cell death. Although infection is incurable, anti-retroviral treatment (ART) can control infection and partially restore the host's CD4+ T cells Despite this success, the virus persists at low levels within lymph nodes suggesting a host reservoir located in the follicular region. More specifically, viral RNA is identified not-only witin CD4 T cells but in follicles and strikingly co-localizes with follicular dendritic cells (FDC). How virus is retained for extensive periods in humans by FDC is not known. FDC are stromal derived and they are required for formation and maintenance of the B cell follicles and for recruitment of CD4+ T follicular helper cells (TFH), the primary target cell of HIV. Recently, we reported that FDC take-up immune complexes via the CD21 receptor and periodically cycle the complexes to the cell surface. Our central hypothesis is that HIV is retained by a similar pathway as immune complexes and that the infectious virus periodically cycles to the FDC surface where it can infect TFH. We will test this hypothesis in the following three aims: AIM 1. Test the hypothesis that FDC (human and non-human primate) endocytose complement-opsonized lentivirus via CD21 and periodically cycle viral complex to the surface. AIM 2. Test hypothesis that FDC isolated from infected individuals transmit infectious virus to CD4+ T cells in vitro and infection can be blocked with a decoy human CD21 receptor. AIM 3. Test efficacy of soluble human CD21 receptor in blockade of SIV retention by FDC and naive B cells in non-human primates. Milestones: The focus for years 1 & 2 (R21 period) is on Aims 1 & 2. The first major milestone is to identify retention of HIV virus by FDC isolated from humans infected with the virus. The second major milestone is the finding that treatment of HIV-infected FDC with a soluble CD21-Ig fusion protein blocks transmission of the virus to non-infected human CD4 T cells in vitro. The third major milestone is that finding that FDC isolated from SIV -infected non-human primates also retain virus and that treatment with sCD21-Ig blocks its transmission to monkey T cells. Aim 3 will be initiated as the R33 Section of the grant if approved by NIAID for years 3-5. The fourth major milestone is demonstration that blockade of C3d-ligand binding to CD21 receptor on FDC and B cells disrupts retention of SIV by FDC in vivo.