Using miRNAs to elucidate the cellular sources of HIV-1

使用 miRNA 阐明 HIV-1 的细胞来源

基本信息

批准号：
8789293
负责人：
Wendy Jean Maury
金额：
$ 25.31万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8789293
关键词：
Acute Address Adverse effects Antiviral Agents Antiviral Therapy Biology CD4 Positive T Lymphocytes Cells Dengue Virus Development Engineering Future Genome Goals HIV HIV Genome HIV Infections HIV-1 Hematopoietic Human Immune response In Vitro Individual Infection Knowledge Lymphoid Mediating MicroRNAs Modeling Molecular Cloning Monitor Myelogenous Pathogenesis Peripheral Blood Lymphocyte Phenotype Population Production Recombinants Regimen Relative (related person)Research Role SCID-hu Mice Sensitivity and Specificity Site Source Specificity Staging T-Lymphocyte Subsets Technology Testing Therapeutic Tissues Tonsil Tropism Viral Viral Load result Viral Pathogenesis Viral load measurement Viremia Virus Virus Diseases Virus Latency Virus Replication cell type cellular targeting chemokine clinically relevant cytokine defined contribution expectation in vivo influenzavirus innovative technologies insight loss of function macrophage monocyte new technology novel strategies novel therapeutics public health relevance response tissue culture tool treatment strategy virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): The relative in vivo contribution of permissive cell populations to HIV-1 viremia and total virus load during acute and subsequent persistent infections is poorly understood. A better understanding of the contribution of tissue macrophages and CD4+ T cell subpopulations will allow a more complete picture of HIV pathogenesis and potentially stimulate the development of cell-specific antiviral approaches that are likely to decrease side effects that are associated with current antiviral therapies. To date, approaches to understand the impact of the different cellular compartments in vivo have been limited and laborious. The novel approach proposed to be developed here will allow the field to clearly define the contribution of these cells to virus load and cytokine/chemokine changes. In these tissue culture and explant studies, we propose to develop a new and innovative technology to control the tropism of HIV for the purposes of delineating the contribution of specific cell types for HIV infection and pathogenesis and provide proof-of-principal that when used in vivo can provide important insights into impact of the cellular reservoirs of HIV. We will engineer recombinant HIV strains that are restricted in either myeloid- or lymphoid-specific cultures by harnessing cell- specific expression of endogenous miRNAs. Through incorporation of perfect miRNA target sites into the HIV genome, expression of these HIVs are restricted in targeted cellular subtypes, thereby allowing us to ascertain the contribution of these cells by a loss of function phenotype. By restricting HIV replication in a variety of different hematopoietic cellular subsets, we will determine how this impacts both virus and host biology in the context of primary ex vivo infections.

描述（由申请人提供）：在急性和随后的持续感染期间，允许细胞群体对HIV-1病毒血症和总病毒负荷的相对体内贡献鲜为人知。更好地理解组织巨噬细胞和CD4+ T细胞亚群的贡献将使HIV发病机理的更完整描述，并有可能刺激细胞特异性抗病毒药物的发展，这些抗病毒药物可能会降低与当前抗病毒药疗法有关的副作用。迄今为止，了解不同细胞隔室在体内影响的方法是有限和费力的。建议在此提出的新方法将使该领域能够清楚地定义这些细胞对病毒载荷和细胞因子/趋化因子变化的贡献。在这些组织培养和外植体研究中，我们建议开发一种新的创新技术，以控制艾滋病毒的向向主义，以描述特定细胞类型对艾滋病毒感染和发病机理的贡献，并提供优质证明，当使用时，可以在体内提供对HIV细胞储藏的重要见解。我们将通过利用内源性miRNA的细胞特异性表达来设计在髓样或淋巴特异性培养物中受到限制的重组HIV菌株。通过将完美的miRNA靶位点掺入HIV基因组中，这些HIV的表达受到靶向细胞亚型的限制，从而使我们能够通过功能表型的丧失来确定这些细胞的贡献。通过限制各种不同造血细胞子集中的HIV复制，我们将在原发性离体感染的背景下确定这如何影响病毒和宿主生物学。