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

基本信息

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
项目类别：
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

项目摘要

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（申请人提供）：世界上大多数新的 HIV-1 感染是由女性在异性接触后获得的。在性传播过程中，HIV-1 必须穿过生殖器粘膜，在早期靶细胞中感染和复制。然后从最初的入侵部位传播，产生全身感染，HIV-1 主要在 CD4+ 淋巴细胞中复制，但已知这些细胞大多不存在于完整的粘膜表面。由于很难分离基于组织的树突状细胞，因此大多数研究采用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。我们开发了新方法，从废弃的阴道组织中分离出基于组织的树突状细胞，称为 CD1a+ 阴道树突状细胞 (VDC)。 VDC 具有独特的细胞表面受体、细胞内特征和敏感性，最重要的是，我们证明能够利用 CCR5 受体（称为 R5）的 HIV-1 能够在 CD1a+ VDC 中复制，而使用 CXCR4 受体（称为 X4）的变体。）无法感染这些细胞，因为新感染受试者获得的病毒主要使用 CCR5 受体，尽管传播伙伴通常同时携带利用病毒粒子的 R5 和 CXCR4，我们的数据解释了这一最基本的情况。我们首先观察到 CD1a+ VDC 将树突投射到阴道腔中，这些树突允许 CCR5 而不是 CXCR4 使用病毒从 CD1a+ VDC 中进行局部复制，从而促进病毒跨粘膜转移。除了增加 HIV-1 在更深的 CD4+ 淋巴细胞中感染和复制的能力之外，我们还发现了这一点。 CD1a+ VDC 还确定哪些 HIV-1 变体在幼稚宿主体内建立有效感染。在性传播过程中，新感染的受试者仅从慢性感染的传播伙伴中传播的多种 X4 和 R5 病毒中获得有限数量的 R5 变体。此外，与传播伙伴中存在的准种相比，感染 R5 的病毒通常具有独特的基因型和表型，我们努力让 CD1a+ VDC 发挥看门人的作用，既阻止 X4 病毒又促进复制。在该提案中，我们将研究使 CD1a+ VDC 对 R5 敏感但对 X4 HIV-1 具有抗性的机制。我们将研究这些细胞是否允许优先复制。我们还将探索能够阻止 CD1a+ VDC 中复制以及病毒转移至 CD4+ T 细胞的抑制剂。 CD1a+ VDC 或病毒转移至 CD4+ T 细胞将提出旨在预防 HIV-1 粘膜传播的新型疫苗和杀菌剂策略。