Characterization of follicular dendritic cells as a reservoir for HIV

滤泡树突状细胞作为 HIV 储存库的特征

• 批准号: 9292724
• 负责人: Michael Craig Carroll
• 金额: $ 44.23万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9292724
• 关键词: Anti-Retroviral Agents; Antibodies; Antigen-Antibody Complex; Antigens; B-Lymphocytes; BLR1 gene; Binding; Biopsy; Blood Cells; CCR5 gene; CD4 Positive T Lymphocytes; CXCL13 gene; CXCR4 gene; Cell Death; Cell surface; Cells; Chimeric Proteins; Coculture Techniques; Complement; Complement 3d; Complement 3d Receptors; Complex; Development; Endocytosis; Figs - dietary; Follicular Dendritic Cells; Grant; Health; Helper-Inducer T-Lymphocyte; Human; Immune; Immune system; Immunohistochemistry; In Situ Hybridization; In Vitro; Individual; Infection; Infection Control; Life; Life Expectancy; Ligand Binding; Lymphoid; Macaca mulatta; Maintenance; Modeling; Monkeys; National Institute of Allergy and Infectious Disease; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Play; Population; Proteins; RNA Viruses; Reporting; Role; SIV; Source; Staging; Stromal Cells; Subfamily lentivirinae; Surface; T-Lymphocyte; Testing; Viral; Viral Load result; Viral reservoir; Viremia; Virion; Virus; Virus Diseases; chemokine; efficacy testing; in vivo; lymph nodes; nonhuman primate; novel; novel strategies; novel therapeutic intervention; receptor; research study; success; trafficking; transmission process; viral RNA; viral transmission

 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.

 描述：人类免疫缺陷病毒(HIV)是一种负链RNA病毒，感染人类CD4+T细胞导致复制和细胞死亡。虽然感染是不可治愈的，但抗逆转录病毒治疗(ART)可以控制感染并部分恢复宿主的CD4+T细胞，尽管取得了这一成功，但病毒在淋巴结内的水平仍然很低，这表明宿主储存在滤泡区。更具体地说，病毒RNA不仅存在于CD4T细胞中，还存在于滤泡中，并与滤泡树突状细胞(FDC)显著地共存。多么 病毒通过FDC在人类体内保留了很长一段时间，目前尚不清楚。FDC来源于基质，是B细胞滤泡的形成和维持以及HIV的主要靶细胞--CD4+T滤泡辅助细胞(TFH)募集所必需的。最近，我们报道了FDC通过CD21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通过与免疫复合体相似的途径保留下来，并且传染性病毒周期性地循环到FDC表面，在那里它可以感染TFH。我们将从以下三个方面对这一假说进行检验：目的1.检验FDC(人类和非人类灵长类)通过CD21内吞补体调理慢病毒的假说，并周期性地将病毒复合体循环到表面。目的2.从感染者体内分离的FDC在体外将传染性病毒传递给CD4+T细胞并感染 可以被诱骗的人CD21受体阻断。目的3.检测可溶性人CD21受体阻断非人类灵长类动物FDC和幼稚B细胞滞留SIV的效果。里程碑：第1年和第2年(R21期间)的重点是AIMS 1和2。第一个主要里程碑是确定从感染病毒的人身上分离的FDC对HIV病毒的保留。第二个重要的里程碑是发现用可溶的CD21-Ig融合蛋白治疗HIV感染的FDC在体外阻止了病毒向未感染的人类CD4T细胞的传播。第三个重要的里程碑是，从感染SIV的非人类灵长类动物中分离出的FDC也保留了病毒，并且用sCD21-Ig治疗阻止了病毒向猴子T细胞的传播。如果NIAID批准，AIM 3将作为赠款的R33部分启动，为期3-5年。第四个重要的里程碑是证明了阻断FDC和B细胞上CD21受体的C3d配体结合破坏了FDC在体内对SIV的保留。