Impact of the gastrointestinal microbiome on HIV reservoirs

抗逆转录病毒治疗 (ART) 可以将艾滋病毒感染者 (PLWH) 的病毒血症降低至不可检测的水平。 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 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来帮助制定有效的艾滋病毒治疗策略 建立和维持细胞储库的生理和代谢过程，以及 那些病毒重新激活的情况。无论 HIV 感染是如何获得的，胃肠道 (GI) 都是一个 HIV复制的主要位点。尽管体内的大多数免疫细胞，包括 CD4 T 细胞， 存在于胃肠道中，但人们对在该组织中建立的艾滋病毒储存库知之甚少。分析 与血细胞相比，接受 ART 治疗的患者胃肠道细胞中的 HIV-DNA 水平更高， 表明存在更大的艾滋病毒储存库。检查血液和直肠细胞中的 HIV 转录本 经 ART 治疗的 PLWH 还表明，胃肠道可能富含潜伏感染细胞，并表明 HIV潜伏期是通过胃肠道中的不同机制维持的和/或更深的潜伏状态 可以维持。基于这些观察，我们的总体假设是艾滋病毒建立了 胃肠道中的潜伏感染导致 ATI 期间病毒反弹。据我们所知有 实际上没有关于微生物组在建立或维持潜在微生物中的作用的信息。 胃肠道中的水库。目前，大量间接证据表明胃肠道微生物组 参与艾滋病毒的持续存在。感染者中的胃肠道微生物组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群和 微生物代谢物可以影响 HIV 转录。因此，我们进一步推测肠道 微生物组有助于艾滋病毒储存库的建立和持续存在，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 对于艾滋病毒治疗的发展至关重要。此前，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，该感染在停止 ART 后产生 病毒强劲反弹。重要的是，我们最近证明了静息状态下可重复诱导 HIV 使用两种不同潜伏期逆转的 ART 抑制人源化小鼠多个组织中的 CD4 T 细胞 接近。我们的目标是使用 BLT 人源化小鼠（一种良好的 HIV潜伏期、持续性和重新激活的特征模型。我们将 1) 分析 HIV 储存库的形成 在胃肠道中，2) 评估胃肠道对病毒反弹的贡献，以及 3) 评估 HIV 诱导 胃肠道通过潜伏期逆转剂。我们还将使用创新的无菌 BLT 小鼠模型来 确定胃肠道微生物组的存在如何促进艾滋病毒的持续存在和反弹。

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.