The Role of Human Gut Microbiota in HIV-1 Rectal Acquisition, Replication, and Pathogenesis

人类肠道微生物群在 HIV-1 直肠获得、复制和发病机制中的作用

• 批准号: 9234472
• 负责人: Angela Raquel Wahl
• 金额: $ 73.08万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234472
• 关键词: Affect; Antibiotics; Bone Marrow; CD4 Positive T Lymphocytes; Cells; Clinical; Data; Dendritic Cells; Diet; Disease; Disease Progression; Enteral; Evaluation; Exhibits; Frequencies; Future; Germ-Free; Gnotobiotic; Goals; HIV; HIV Infections; HIV-1; Hematopoietic; Home environment; Human; Human Microbiome; Human poliovirus; Immune; Immunity; Individual; Infection; Inflammation; Injury; Interdisciplinary Study; Intervention; Knowledge; Liver; Modeling; Mouse Mammary Tumor Virus; Mouse Strains; Mucosal Immunity; Mus; Norovirus; Operative Surgical Procedures; Organism; Pathogenesis; Pathogenicity; Patients; Phenotype; Population; Predisposition; Prevention; Prevention strategy; Reoviridae; Reovirus; Ribosomal RNA; Risk; Role; Route; Sampling; Site; Stress; Structure; Symbiosis; System; T-Lymphocyte; Therapeutic; Thymus Gland; Tissues; United States; Virus; Virus Replication; base; clinical development; cohort; gut microbiome; gut microbiota; humanized mouse; in vivo; in vivo Model; innovation; macrophage; microbial; microbial community; microbiome; microbiota; microorganism; mouse model; novel; prevent; public health relevance; reconstitution; rectal; transmission process

 DESCRIPTION (provided by applicant): The gut is an important site of HIV acquisition. The majority of new HIV infections in the United States are acquired rectally, and rectal transmission of HIV is a significant mode of HIV acquisition globally. The gut is also a significant site of virs replication, CD4+ T cell depletion, inflammation and microbial translocation. Commensal gut microbiota protect the gut from infection by pathogenic organisms, however, gut microbiota can facilitate the transmission and pathogenesis of certain viruses that target the gut (i.e. polioviru, norovirus, reovirus, mouse mammary tumor virus). The effect of gut microbiota on HIV acquisition risk and other aspects of HIV infection is not known. Our long-term goal is to establish how gut microbiota affect HIV acquisition, pathogenesis, latency, treatment and prevention. The direct experimentation that is needed to establish the role of human gut microbiota in HIV-1 acquisition and infection is not possible to perform in humans. Bone marrow/liver/thymus (BLT) humanized mice are systemically reconstituted with human immune cells and have been extensively utilized to study HIV transmission, pathogenesis and prevention strategies in vivo. However, the gut microbiome of BLT mice is murine. Recently, we rederived and utilized a germ-free immune deficient mouse strain to generate germ-free BLT mice that can be colonized with human gut microbiota (HuM-BLT mice). Our objective here is implement these novel and innovative in vivo models that we recently developed to evaluate the role of gut microbiota in rectal HIV-1 acquisition as the first step towards achieving this goal. Our preliminary data demonstrate: 1) robust systemic reconstitution of germ-free BLT mice with human HIV target cells; 2) the gut microbiome of HuM-BLT mice is stable and recapitulates the human donor inoculum; 3) HuM- BLT mice are susceptible to rectal HIV acquisition; and 4) the presence of human gut microbiota significantly increases rectal HIV acquisition in HuM-BLT mice in comparison to BLT mice with mouse microbiota (MM-BLT mice) (p=0.01). Based on our preliminary data, we hypothesize that the composition of the gut microbiome affects the rectal HIV-1 transmission risk. We will establish the full extent and utility of HuM-BLT mice for the study of the human gut microbiome and its role in rectal HIV-1 acquisition by generating multiple cohorts of HuM-BLT mice colonized with the gut microbiome of different healthy human donors and by 1) assessing the effect of human microbial diversity on gut microbiota colonization in HuM-BLT mice, 2) determining the effect of human gut microbiota on systemic reconstitution, maturation and activation of HIV-susceptible cells in HuM- BLT mice and 3) evaluating the role of gut microbiota in rectal HIV-1 acquisition, replication and pathogenesis. The information obtained will fill an important void in our knowledge regarding the role of human gut microbiota in rectal HIV-1 acquisition that in turn will serve to inform future clinical interventions aimed a preventing rectal HIV-1 transmission. These results will also validate HuM-BLT mice as an in vivo platform for the study of the human gut microbiome and for the evaluation of HIV infection in the context of human gut microbiota.

 描述（由应用程序提供）：肠道是艾滋病毒收购的重要地点。美国大多数新的艾滋病毒感染是直接获得的，艾滋病毒的直肠传播是全球艾滋病毒收购的一种重要模式。肠道也是VIRS复制，CD4+ T细胞部署，感染和微生物翻译的重要部位。但是，共生肠道菌群可保护肠道免受致病生物的感染，但是，肠道菌群可以促进靶向肠道的某些病毒的传播和发病机理（即polioviru，norovirus，norovirus，sovirus，eovivirus，依默伏病毒，e依病毒，小鼠哺乳动物肿瘤病毒）。肠道微生物群对HIV获取风险和HIV感染的其他方面的影响尚不清楚。我们的长期目标是确定肠道菌群如何影响艾滋病毒的获取，发病机理，潜伏期，治疗和预防。建立人肠道微生物群在HIV-1获取和感染中的作用所需的直接实验是在人类中无法进行的。骨髓/肝脏/胸腺（BLT）人源化小鼠是通过人类免疫细胞系统地重构的，并且已广泛用于研究体内的HIV传播，发病机理和预防策略。但是，BLT小鼠的肠道微生物组是鼠。最近，我们重新维修和利用了无菌免疫缺陷的小鼠菌株，以产生可以用人肠道微生物群（HUM-BLT小鼠）定殖的无细菌BLT小鼠。我们在这里的目标是实施了这些新颖和创新的体内模型，我们最近开发了肠道菌群在直肠HIV-1获取中的作用，作为实现这一目标的第一步。我们的初步数据证明了：1）使用人类艾滋病毒靶细胞对无细菌BLT小鼠的稳健全身重构； 2）Hum-Blt小鼠的肠道微生物组是稳定的，并概括了人类供体接种物； 3）HUM-BLT小鼠容易受到直肠HIV的感染； 4）与用小鼠微生物群（MM-BLT小鼠）相比，人类肠道微生物群的存在显着增加了HUM-BLT小鼠中直肠HIV的获取（P = 0.01）。根据我们的初步数据，我们假设肠道微生物组的组成会影响直肠HIV-1传输风险。我们将通过产生与不同健康人供体的肠道微生物组的多个同类群体来建立HUM-BLT小鼠在研究人肠道微生物组及其在直肠HIV-1获取中的作用的全部程度和实用性，并通过1）评估人类微生物微生物对人类微生物的效应的作用。全身重构，HIM-BLT小鼠中HIV爆发细胞的成熟和激活以及3）评估肠道菌群在直肠HIV-1采集，复制和发病机理中的作用。获得的信息将填补我们关于人类肠道微生物群在直肠HIV-1获取中的作用的重要空白，而直肠HIV-1获取中的作用将有助于未来的临床干预措施，以防止直肠HIV-1传播。这些结果还将验证HUM-BLT小鼠作为研究人肠道微生物组研究的体内平台，并在人肠道微生物群中评估HIV感染。