Impact of the gastrointestinal microbiome on HIV reservoirs

胃肠道微生物组对 HIV 储存库的影响

• 批准号: 10669232
• 负责人: J. Victor Garcia-Martinez
• 金额: $ 13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669232
• 关键词: Address; BLT mice; Binding; Biological Models; Blood; Blood Cells; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Separation; Cells; DNA; Development; Disease remission; Frequencies; Gastrointestinal tract structure; Genetic Transcription; Germ-Free; Gnotobiotic; Goals; HIV; HIV Core Protein p24; HIV Infections; Histone Acetylation; Histone Deacetylase Inhibitor; Immune; In Vitro; Infection; Inflammation; Interruption; Intestinal Mucosa; Intestines; Kinetics; Knowledge; Lymphocyte; Maintenance; Metabolism; Modeling; Mucosal Immunity; Pathogenesis; Pathway interactions; Patients; Persons; Physiological Processes; Plasma; Process; RNA; Rectum; Reporting; Reproducibility; Research; Rest; Role; Site; Tissues; Transcript; Viral; Viremia; Virus; antiretroviral therapy; dysbiosis; efficacy evaluation; gut microbiome; humanized mouse; immune activation; in vivo; in vivo Model; innovation; latent infection; microbial; microbial products; microbiome; microbiota; mouse model; multidisciplinary; peripheral blood; rectal; viral rebound; virtual

Antiretroviral therapy (ART) can reduce viremia to undetectable levels in people living with HIV (PLWH) . However, replication-competent virus persists in peripheral blood and tissues that is capable of reestablishing the infection upon antiretroviral therapy interruption (ATI). One of our long-term goals is to aid the development of effective HIV cure strategies by gaining a better understanding of the host physiological and metabolic processes by which cellular reservoirs are established and maintained, and those of viral reactivation. Regardless of how HIV infection is acquired, the gastrointestinal (GI) tract is a major site of HIV replication. Although the majority of immune cells in the body, including CD4+ T cells, reside in the GI tract, little is known about the HIV reservoir that is established in this tissue. Analyses of ART-treated patients have demonstrated higher HIV-DNA levels in GI tract cells compared to blood cells, suggestive of a larger HIV reservoir. Examination of HIV transcripts in cells from the blood and rectum of ART-treated PLWH also indicates that the GI tract may be enriched in latently-infected cells and suggests that HIV latency is maintained by different mechanisms in the GI tract and/or that a deeper s tate of latency may be maintained. Based on these observations, our overarching hypothesis is that HIV establishes a latent infection in the GI tract that contributes to virus rebound during ATI. T o our knowledge there is virtually no information addressing the role of the microbiome in establishing or maintaining the latent reservoir in the GI tract. Currently, a large amount of indirect evidence suggests that the GI microbiome is involved in HIV persistence. The GI microbiome in PLWH promotes inflammation and immune activation in the GI tract, which may influence HIV reservoir size. Furthermore, in vitro studies show that microbiota and microbial metabolites can influence HIV transcription. Therefore, we further hypothesize that the intestinal microbiome contributes to the establishment and persistence of the HIV reservoir and thereby impacts the contribution of the GI tract to virus rebound. A role for the microbiome in HIV remission would be fundamentally important to HIV cure development. Previously, we and others demonstrated that HIV establishes a latent infection in ART-suppressed humanized mice that upon discontinuation of ART results in robust virus rebound. Importantly, we recently demonstrated reproducible induction of HIV in resting CD4+ T cells in multiple tissues of ART-suppressed humanized mice using two different latency reversal approaches. Our objective is to analyze the HIV reservoir in the GI tract using BLT humanized mice, a well- characterized model of HIV latency, persistence and reactivation. We will 1) analyze HIV reservoir formation in the GI tract, 2) evaluate the contribution of the GI tract to viral rebound, and 3) assess HIV induction in the Gl tract by latency reversing agents. We will also use an innovative germ-free BLT mouse model to determine how the presence of the GI microbiome contributes to HIV persistence and rebound.

抗逆转录病毒疗法(ART)可以将艾滋病毒携带者(PLWH)的病毒血症降低到无法检测到的水平。 然而，具有复制能力的病毒持续存在于外周血和组织中，能够 在抗逆转录病毒治疗中断(ATI)后重建感染。我们的长期目标之一是 通过更好地了解宿主，帮助制定有效的艾滋病毒治疗策略 建立和维持细胞储存库的生理和代谢过程，以及 病毒重新激活的那些。无论艾滋病毒是如何感染的，胃肠道(GI)都是一种 艾滋病毒复制的主要地点。尽管体内的大多数免疫细胞，包括CD4+T细胞， 居住在胃肠道中，人们对这种组织中建立的艾滋病毒储存库知之甚少。分析了 接受抗逆转录病毒治疗的患者胃肠道细胞中的HIV-DNA水平高于血细胞， 暗示着有一个更大的艾滋病毒储存库。猪血液和直肠细胞中HIV转录本的检测 经ART治疗的PLWH还表明，胃肠道可能富含潜伏感染的细胞，并提示 艾滋病毒的潜伏期由胃肠道中的不同机制维持和/或S潜伏期的更深层次 可能会维持下去。基于这些观察，我们的首要假设是，艾滋病毒建立了一种 胃肠道的潜伏感染，导致ATI期间病毒反弹。据我们所知，有 几乎没有关于微生物组在建立或维持潜伏期的作用的信息 胃肠道的蓄水池。目前，大量间接证据表明，胃肠道微生物群是 参与艾滋病毒的持久化。PLWH中的GI微生物群促进炎症和免疫激活 胃肠道，这可能会影响HIV储存库的大小。此外，体外研究表明，微生物区系和 微生物代谢产物会影响HIV的转录。因此，我们进一步假设，肠道 微生物组有助于艾滋病毒储存库的建立和持续，从而影响 胃肠道对病毒反弹的贡献。微生物群在艾滋病毒缓解中的作用将是 对艾滋病毒治疗的发展具有根本性的重要意义。此前，我们和其他人证明了艾滋病毒 在ART抑制的人源化小鼠中建立潜伏感染，在停止ART结果时 病毒强劲反弹。重要的是，我们最近证明了在休息时可重复地诱发艾滋病毒。 两种不同潜伏期逆转方法对ART抑制人源化小鼠多组织中CD4+T细胞的影响 接近了。我们的目标是利用BLT人源化小鼠来分析胃肠道内的HIV储存库，这是一种很好的- 表征了HIV潜伏期、持久性和重新激活的模型。我们将1)分析HIV病毒宿主的形成 在胃肠道，2)评估胃肠道对病毒反弹的贡献，以及3)评估艾滋病毒在 潜伏期反转剂作用于Gl区。我们还将使用一种创新的无菌BLT小鼠模型来 确定胃肠道微生物群的存在如何有助于艾滋病毒的持续和反弹。