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: 10374223
• 负责人: J. Victor Garcia-Martinez
• 金额: $ 77.7万
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374223
• 关键词: Address; BLT mice; Biological Models; Blood; Blood Cells; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; DNA; Development; Disease remission; Frequencies; Gastrointestinal tract structure; Genetic Transcription; Germ-Free; Gnotobiotic; Goals; HIV; HIV Core Protein p24; HIV Infections; Histone Deacetylase Inhibitor; Histones; Immune; In Vitro; Infection; Inflammation; Interruption; Intestinal Mucosa; Intestines; Kinetics; Knowledge; Lymphocyte; Maintenance; Metabolism; Modeling; Mucosal Immunity; Pathogenesis; Pathway interactions; Patients; Peripheral; Physiological Processes; Plasma; Process; RNA; Rectum; Reporting; Reproducibility; Research; Rest; Role; Site; Suggestion; Tissues; Transcript; Viral; Viremia; Virus; antiretroviral therapy; base; dysbiosis; gut microbiome; humanized mouse; immune activation; in vivo; in vivo Model; innovation; latent infection; microbial; microbiome; microbiota; mouse model; multidisciplinary; peripheral blood; 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）可以将病毒血症降低到艾滋病毒（PLWH）患者的无法检测到的水平。 但是，复制能力的病毒持续存在于外周血和组织中 在抗逆转录病毒治疗中断（ATI）时重新建立感染。我们的长期目标之一是 通过更好地了解主机来帮助制定有效的HIV治疗策略 建立和维护细胞储层的生理和代谢过程， 病毒重新激活的。无论如何获得HIV感染，胃肠道（GI）是一个 HIV复制的主要部位。尽管体内的大多数免疫细胞，包括CD4+ T细胞，但 居住在胃肠道中，对在该组织中建立的HIV储层知之甚少。分析 与血细胞相比 暗示更大的艾滋病毒储量。检查来自血液和直肠细胞中的HIV转录本 ART处理的PLWH还表明，胃肠道可能富含潜在感染的细胞，并建议 艾滋病毒潜伏期是通过胃肠道和/或更深的潜伏期中的不同机制维持的 可以维护。基于这些观察，我们的总体假设是HIV建立了一个 胃肠道的潜在感染会导致ATI期间病毒反弹。我们的知识有 几乎没有信息可以解决微生物组在建立或维护潜伏的角色中的作用 胃肠道中的水库。目前，大量间接证据表明，胃肠道微生物组是 参与艾滋病毒的持久性。 PLWH中的GI微生物组促进了炎症和免疫激活 胃肠道可能影响HIV储层的大小。此外，体外研究表明，微生物群和 微生物代谢物可以影响HIV转录。因此，我们进一步假设肠道 微生物组有助于艾滋病毒水库的建立和持久性，从而影响 胃肠道对病毒反弹的贡献。微生物组在HIV缓解中的作用将是 对于艾滋病毒治愈的发展至关重要。以前，我们和其他人证明了艾滋病毒 建立一种在艺术抑制的人源性小鼠中的潜在感染，该小鼠在停止艺术结果后 在健壮的病毒反弹中。重要的是，我们最近证明了HIV静止的可重复诱导 使用两种不同的潜伏期逆转，Art抑制的人源性小鼠的多个组织中的CD4+ T细胞 方法。我们的目的是使用BLT人源化小鼠（一种井）分析胃肠道中的艾滋病毒储量 艾滋病毒潜伏期，持久性和重新激活的特征模型。我们将1）分析艾滋病毒储量形成 在胃肠道中，2）评估胃肠道对病毒反弹的贡献，3）评估HIV诱导 延迟逆转代理的GL道。我们还将使用创新的无菌BLT鼠标模型 确定GI微生物组的存在如何有助于HIV持久性和反弹。