Impact of the gastrointestinal microbiome on HIV reservoirs

抗逆转录病毒疗法（ART）可以将艾滋病毒感染者（PLWH）的病毒血症降低到无法检测的水平。 然而，有复制能力的病毒持续存在于外周血和组织中，其能够 在抗逆转录病毒治疗中断（ATI）后重新建立感染。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 生理和代谢过程，通过这些过程细胞储库得以建立和维持，以及 病毒再激活的那些。无论艾滋病毒感染是如何获得的，胃肠道（GI）是一个 HIV复制的主要场所。虽然体内的大多数免疫细胞，包括CD 4 + T细胞， 虽然HIV病毒存在于胃肠道，但人们对在该组织中建立的HIV储存库知之甚少。分析 ART治疗的患者已经证明胃肠道细胞中的HIV-DNA水平高于血细胞， 暗示着更大的艾滋病病毒库从血液和直肠的细胞中检测HIV转录本 ART治疗的PLWH也表明胃肠道可能富含潜伏感染的细胞，并提示 HIV潜伏期由胃肠道中的不同机制维持，和/或潜伏期的更深状态 可以保持。基于这些观察，我们的总体假设是，艾滋病毒建立了一个 胃肠道潜伏感染，导致ATI期间病毒反弹。据我们所知， 几乎没有关于微生物组在建立或维持潜在的 胃肠道中的储库。目前，大量间接证据表明，胃肠道微生物组是 参与了艾滋病的持久性。PLWH中的GI微生物组促进炎症和免疫激活， 胃肠道，这可能会影响艾滋病毒水库的大小。此外，体外研究表明， 微生物代谢物可以影响HIV的转录。因此，我们进一步假设， 微生物组有助于艾滋病毒宿主的建立和持续存在，从而影响 胃肠道对病毒反弹的贡献。微生物组在艾滋病毒缓解中的作用是 对艾滋病治疗的发展至关重要。以前，我们和其他人证明，艾滋病毒 在ART抑制的人源化小鼠中建立潜伏感染， 病毒的强劲反弹。重要的是，我们最近证明了在静息状态下HIV的可重复诱导， 使用两种不同的潜伏期逆转，ART抑制的人源化小鼠的多种组织中的CD 4 + T细胞 接近。我们的目标是使用BLT人源化小鼠分析胃肠道中的HIV储库， 艾滋病毒潜伏期、持久性和再激活的特征模型。我们将1）分析艾滋病毒储库的形成 2）评价胃肠道对病毒反弹的贡献，3）评估 胃肠道潜伏期逆转剂。我们还将使用一种创新的无菌BLT小鼠模型， 确定胃肠道微生物组的存在如何有助于艾滋病毒的持久性和反弹。

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.