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（由申请人提供）：肠道是HIV感染的重要部位。在美国，大多数新的HIV感染是通过直肠获得的，并且HIV的直肠传播是全球HIV获得的重要模式。肠道也是病毒复制、CD 4 + T细胞耗竭、炎症和微生物易位的重要场所。肠道微生物群保护肠道免受病原微生物的感染，然而，肠道微生物群可以促进靶向肠道的某些病毒（即脊髓灰质炎病毒、诺如病毒、呼肠孤病毒、小鼠乳腺肿瘤病毒）的传播和发病。肠道微生物群对艾滋病毒感染风险和艾滋病毒感染其他方面的影响尚不清楚。我们的长期目标是确定肠道微生物群如何影响HIV的获得、发病机制、潜伏期、治疗和预防。需要建立人类肠道微生物群在HIV-1获得和感染中的作用的直接实验不可能在人类中进行。骨髓/肝脏/胸腺（BLT）人源化小鼠用人免疫细胞全身重建，并且已被广泛用于研究体内HIV传播、发病机制和预防策略。然而，BLT小鼠的肠道微生物组是鼠类的。最近，我们重新衍生并利用无菌免疫缺陷小鼠品系来产生可以用人类肠道微生物群定殖的无菌BLT小鼠（HuM-BLT小鼠）。我们的目标是实施我们最近开发的这些新颖和创新的体内模型，以评估肠道微生物群在直肠HIV-1获得中的作用，作为实现这一目标的第一步。我们的初步数据表明：1）用人HIV靶细胞对无菌BLT小鼠进行稳健的全身性重建; 2）HuM-BLT小鼠的肠道微生物组是稳定的并且重现了人供体接种物; 3）HuM-BLT小鼠对直肠HIV获得敏感;和4）与具有小鼠微生物群的BLT小鼠相比，人肠道微生物群的存在显著增加了HuM-BLT小鼠中的直肠HIV获得（MM-BLT小鼠）（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影响直肠HIV-1传播风险。我们将通过产生用不同健康人类供体的肠道微生物组定殖的多个HuM-BLT小鼠群组和通过1）评估人类微生物多样性对HuM-BLT小鼠中肠道微生物群定殖的影响，2）确定人类肠道微生物群对HuM-BLT小鼠中HIV易感细胞的系统性重建、成熟和激活的影响，以及3）评估肠道微生物群在直肠HIV-1获得、复制和发病机制中的作用。所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获得中的作用的知识中的一个重要空白，这反过来将为未来旨在预防直肠HIV-1传播的临床干预提供信息。这些结果还将验证HuM-BLT小鼠作为研究人类肠道微生物组和在人类肠道微生物群背景下评估HIV感染的体内平台。