CD1a Vaginal Dendritic Cells and HIV-1 Acquisition in the Female Genital Tract

CD1a 阴道树突状细胞和女性生殖道中 HIV-1 的获得

• 批准号: 8846903
• 负责人: Manish Sagar
• 金额: $ 44.57万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846903
• 关键词: Antibodies; Antigens; Apical; Birbeck Granule; C Type Lectin Receptors; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 Receptors; CXCR4 gene; Cell Lineage; Cell Surface Receptors; Cell physiology; Cells; Cervical; Characteristics; Charge; Chemokine (C-C Motif) Receptor 5; Chronic; Coculture Techniques; Data; Dendrites; Dendritic Cells; Dermis; Electron Microscopy; Epithelial; Epithelium; Event; Exclusion; Female; Generations; Genetic; Genital system; Genotype; Goals; HIV-1; Heterosexuals; Individual; Infection; Infection prevention; Interferons; Langerhans cell; Length; Lymphocyte; Methods; Modeling; Mucous Membrane; Outcome; Phenotype; Play; Predisposition; Process; Production; Property; Relative (related person); Resistance; Role; Sexual Transmission; Site; Skin; Surface; Systemic infection; T-Lymphocyte; Tissues; V3 Loop; Vagina; Variant; Virion; Virus; Virus Replication; Western Blotting; Woman; Work; adaptive immunity; base; chemokine; cytokine; immunological synapse; inhibitor/antagonist; langerin; microbicide; microorganism; monocyte; novel; novel vaccines; prevent; public health relevance; receptor; sexual encounter; transmission process

 DESCRIPTION (provided by applicant): The majority of new HIV-1 infections in the world are acquired by women after heterosexual contact. During sexual transmission, HIV-1 must get across the genital mucosa, infect and replicate in the early target cells, and then disseminate from the initial site of invasion to generate a systemic infection. HIV-1 primarily replicates in CD4+ lymphocytes, but these cells are mostly absent from intact mucosal surfaces. Tissue based dendritic cells (DCs), known as Langerhans cells (LCs), are generally believed to facilitate HIV-1 access to CD4+ T cells. Because it has been difficult to isolate tissue based dendritic cells, most studies employ monocyte derived dendritic cells (MDDCs) or skin derived LC as surrogates. We have developed novel methods to isolate tissue based dendritic cells termed CD1a+ vaginal dendritic cells (VDCs) from discarded vaginal tissue. The previously uncharacterized CD1a+ VDCs possess unique cell surface receptors, intracellular features and susceptibility. Most importantly, we show that HIV-1, able to utilize the CCR5 receptor, (termed R5) is able to replicate in CD1a+ VDCs while variants that use the CXCR4 receptor (termed X4) fail to infect these cells. Because viruses acquired by newly infected subjects predominantly use the CCR5 receptor although transmitting partners often harbor both R5 and CXCR4 utilizing virions, our data explains this most fundamental observation about coreceptor restriction during HIV-1 acquisition. We hypothesize that CD1a+ VDC project dendrites into the vaginal lumen. These dendrites allow CCR5 but not CXCR4 using viruses to be acquired from the vaginal lumen. Local replication in CD1a+ VDCs facilitates virus transfer across the mucosal epithelium to deeper lying CD4+ T cells. Besides increasing HIV-1's ability to infect and replicate in deeper lying CD4+ lymphocytes, we hypothesize that CD1a+ VDCs also determine which HIV-1 variants establish a productive infection within a naive host. During sexual transmission, a newly infected subject acquires only a limited number of R5 variants from the diverse X4 and R5 viruses circulating in the chronically infected transmitting partner. In addition, infecting R5 viruses often have unique genotypes and phenotypes compared to the quasispecies present in the transmitting partner. We hypothesize that CD1a+ VDCs function as gate keepers, both blocking X4 viruses and favoring the replication of R5 variants with properties often found among HIV-1 isolated early after infection. In the proposal, we will examine mechanisms that allow CD1a+ VDC to be susceptible to R5 but resistant to X4 HIV-1. We will examine if these cells allow preferential replication of the infecting strains compared to non-transmitted viruses. We will also explore inhibitors that can prevent replication in CD1a+ VDCs and transfer of virus to CD4+ T cells. Delineating the mechanistic details and factors that can prevent infection in CD1a+ VDCs or virus transfer to CD4+ T cells will suggest novel vaccine and microbicide strategies aimed at preventing HIV-1 mucosal transmission.

 描述（由适用提供）：世界上大多数新的HIV-1感染是在异性恋接触后获得的。在性传播过程中，HIV-1必须跨越生殖器粘膜，在早期靶细胞中感染和复制，然后从入侵的最初部位传播以产生全身感染。 HIV-1主要在CD4+淋巴细胞中复制，但是这些细胞大多不存在完整的粘膜表面。通常认为，基于组织的树突状细胞（DC），称为兰格汉细胞（LCS），可以促进HIV-1进入CD4+ T细胞。由于很难分离基于组织的树突状细胞，因此大多数研究员工单核细胞衍生的树突状细胞（MDDC）或皮肤衍生的LC作为替代物。我们开发了新的方法来分离从丢弃的阴道组织中分离出称为CD1A+阴道树突状细胞（VDC）的基于组织的树突状细胞。先前未表征的CD1A+ VDC潜在的独特细胞表面受体，细胞内特征和敏感性。最重要的是，我们表明能够使用CCR5受体的HIV-1（称为R5）能够在CD1A+ VDC中复制，而使用CXCR4受体（称为X4）的变体未能感染这些细胞。由于新感染受试者获得的病毒主要使用CCR5受体，尽管传播伴侣经常携带R5和CXCR4利用病毒，因此我们的数据解释了对HIV-1释放期间对核能受体限制的最基本观察。我们假设CD1A+ VDC项目树突进入阴道腔。这些树突允许使用病毒从阴道腔中获取CCR5，但不能使用CXCR4。 CD1A+ VDC中的局部复制促进了病毒转移到粘膜上皮到更深的CD4+ T细胞。除了提高HIV-1在更深层次的CD4+淋巴细胞中感染和复制的能力外，我们假设CD1A+ VDC还确定了哪些HIV-1变体在幼稚宿主中建立了生产性感染。在性传播期间，新感染的受试者仅从慢性感染的传播伴侣中循环的潜水员X4和R5病毒中获得有限数量的R5变体。此外，与传输伴侣中存在的准蛋白相比，受感染的R5病毒通常具有独特的基因型和表型。我们假设CD1A+ VDCS充当栅极守护者，既可以阻止X4病毒，又有利于在感染后早期分离的HIV-1中经常发现的R5变体的复制。在该提案中，我们将检查允许CD1A+ VDC容易受到R5但对X4 HIV-1的抗性的机制。我们将检查这些细胞是否允许与非传播病毒相比，是否允许对感染菌株进行优先复制。我们还将探索可以防止CD1A+ VDC复制并将病毒转移到CD4+ T细胞中的抑制剂。描述可以防止CD1A+ VDC或病毒转移到CD4+ T细胞中感染的机械细节和因素，将表明旨在防止HIV-1粘膜传播的新型疫苗和杀菌剂策略。