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：人免疫缺陷病毒（HIV）是一种阴性的RNA病毒，感染了人CD4+ T细胞，导致复制和细胞死亡。尽管感染是无法治愈的，但抗逆转录病毒治疗（ART）仍可以控制感染并部分恢复宿主的CD4+ T细胞，尽管成功，但该病毒在淋巴结内持续较低，表明位于卵泡区域的宿主储层。更具体地说，病毒RNA被鉴定出不仅损伤的CD4 T细胞，而是在卵泡中鉴定出与卵泡树突状细胞（FDC）的惊人共定位。如何 FDC在人类中保留了很长时间的病毒。 FDC是基质得出的，它们是B细胞随访和募集CD4+ T卵泡辅助细胞（TFH）的形成和维持所必需的，这是HIV的主要靶细胞。最近，我们报道了FDC通过CD21受体采取免疫复合物，并将复合物定期循环到细胞表面。我们的中心假设是，HIV被与免疫复合物相似的途径保留，并且传染病在周期性地循环到FDC表面，在那里它可以感染TFH。我们将在以下三个目的中检验这一假设：目标1。检验FDC（人类和非人类灵长类动物）内吞作用良好的易生病毒的假设，并通过CD21定期循环病毒复合物。 AIM 2。检验假设，即从感染个体中分离出的FDC将感染性病毒传播到CD4+ T细胞的体外和感染 可以用诱饵人CD21受体阻塞。 AIM 3。固体人CD21受体在FDC和Naive B细胞封锁非人类隐私中的SIV保留率中的测试效率。里程碑：1＆2年度（R21时期）的重点是目标1和2。第一个主要里程碑是通过从感染该病毒感染的人类中分离出的FDC来确定FDC对HIV病毒的保留。第二个主要里程碑是发现，通过固体CD21-Ig融合蛋白阻断病毒将病毒传播到未感染的人CD4 T细胞的体外，对HIV感染的FDC进行处理。第三个主要里程碑是发现从SIV感染的非人类私人物中分离出的FDC也保留了病毒，并且用SCD21-IG处理将其传播到猴子T细胞。如果由NIAID批准为3 - 5年，将启动AIM 3作为赠款的R33部分。第四个主要里程碑是证明了FDC上与CD21受体结合的C3D-配体结合的封锁和B细胞在体内破坏了FDC对SIV的保留。