Role of IL-7 and Integrin alpha4beta7 in Human Immunodeficiency Virus Infection

白细胞介素-7（IL-7）是体内主要的T细胞稳态因子，在淋巴细胞减少症（淋巴细胞丢失）发生时，对重建正常的T淋巴细胞池至关重要。我们以前的工作表明，IL-7是主要肠道归巢整合素α 4 β 7（a4 b7）的有效诱导剂，从而将原始T细胞重定向到肠道，这是HIV-1复制的主要解剖部位。此外，我们发现，a4 b7被纳入HIV-1病毒粒子从感染细胞的出口。掺入病毒体的a4 b7具有功能活性，因为它能够结合其天然配体MAdCAM-1，并促进小鼠模型中HIV-1病毒颗粒的肠道归巢。重要的是，a4 b7掺入也发生在体内HIV感染的患者和SIV感染的猕猴，这表明它可能是一个关键的毒力因子，促进和维持HIV-1感染的肠道隔室，特别是在HIV-1感染的早期阶段。我们还证明了另一种宿主受体，P-选择素糖蛋白配体-1（PSGL-1/CD 162），在体外和体内都被纳入HIV-1病毒粒子。我们已经开始调查是否SIV病毒粒子包含纳入a4 b7有一个增加的能力，介导的病毒传播的猕猴模型。因此，产生了具有或不具有掺入的a4 b7的SIVmac 239的同质分子克隆，并用于通过雌性猕猴中的阴道途径的传播研究。初步结果表明，存在纳入a4 b7可能会促进感染，即使在不同的猕猴传播是高度可变的，如预期的研究与远交动物。进一步的研究正在进行中，以评估a4 b7掺入所带来的优势是否对SIV通过直肠内途径传播更重要。 关于IL-7，我们已经发现了这种细胞因子的新功能，通过显示在超稳态浓度下，IL-7是抗HIV趋化因子的有效诱导剂（即，RANTES/CCL 5、MIP-1a/CCL 3和MIP-1b/CCL 4）和其他参与抗微生物免疫应答的细胞因子。这种效应在没有任何其他伴随刺激的情况下发生，但需要T细胞和单核细胞之间的主动和接触依赖性串扰。对介导这种IL-7效应的机制的深入表征已经证明了TNF-α的关键作用。我们还表征了介导IL-7效应的信号转导，并进行了RNAseq分析，这揭示了旨在抗菌防御准备的基因表达的复杂程序。我们已经重新评估了来自我们10年前在猕猴中进行的体内IL-7治疗的研究的微阵列结果（Vassena等人，PLoS Path 2012），并发现在猕猴模型中，许多在体外被IL-7激活的基因也在体内被诱导。最后，我们已经开始研究干扰素-α作为IL-7作用的潜在拮抗剂的作用。总的来说，我们的研究结果表明，IL-7启动了一个程序的免疫防御入侵的微生物通过多种细胞因子和趋化因子的协同招聘。这些结果说明了一种新的潜在的抗菌控制机制，不需要触发一个完整的T细胞活化程序，身体可以在淋巴细胞减少的条件下实施，试图重建失去的免疫功能，以及促进非细胞溶解免疫介导的HIV-1抑制。

Interleukin-7 (IL-7) is the principal T-cell homeostatic factor in the body and is critical to reconstitute the normal T-lymphocyte pool when lymphopenia (loss of lymphocytes) occurs. Our previous work demonstrated that IL-7 is a potent inducer of the main gut-homing integrin, alpha4beta7 (a4b7), and thereby redirects nave T cells to the intestine, which is a primary anatomical site for HIV-1 replication. Furthermore, we found that a4b7 is incorporated into the HIV-1 virion during its egress from infected cells. Virion-incorporated a4b7 is functionally active as it is able to bind to its natural ligand, MAdCAM-1, and promote gut homing of HIV-1 viral particles in a mouse model. Importantly, a4b7 incorporation also occurs in vivo in HIV-infected patients and SIV-infected macaques, suggesting that it may be a critical virulence factor that promotes and sustains HIV-1 infection of the gut compartment, particularly during the early phases of HIV-1 infection. We have also demonstrated that another host receptor, P-selectin glycoprotein ligand-1 (PSGL-1/CD162), is incorporated into HIV-1 virions both in vitro and in vivo. We have started to investigate whether SIV virions containing incorporated a4b7 have an increased capacity to mediate viral transmission in a macaque model. Thus, a homogeneous molecular clone of SIVmac239 was produced either with or without incorporated a4b7 and used for transmission studies by the vaginal route in female macaques. Preliminary results suggest that the presence of incorporated a4b7 may facilitate infection, even though transmission was highly variable in different macaques, as expected in studies with outbred animals. Further studies are ongoing to evaluate if the advantage conferred by a4b7 incorporation may be more significant upon SIV transmission by the intrarectal route. With regard to IL-7, we have discovered a new function of this cytokine, by showing that, at suprahomeostatic concentrations, IL-7 is a potent inducer of anti-HIV chemokines (i.e., RANTES/CCL5, MIP-1a/CCL3 and MIP-1b/CCL4) and other cytokines involved in antimicrobial immune responses. This effect occurs in the absence of any other concomitant stimulation but requires an active and contact-dependent cross-talk between T cells and monocytes. An in-depth characterization of the mechanisms that mediate this IL-7 effect has demonstrated a key role of TNF-alpha. We have also characterized the signal transduction that mediates the IL-7 effects and performed RNAseq analysis, which has unraveled a complex program of gene expression aimed at antimicrobial defense readiness. We have re-evaluated the microarray results from a study of in vivo IL-7 treatment that we had performed in macaques 10 years ago (Vassena et al., PLoS Path 2012) and found that many of the genes activated in vitro by IL-7 are also induced in vivo in the macaque model. Finally, we have started to study the effect of interferon-alpha as a potential antagonist of the IL-7 effects. Overall, our results demonstrate that IL-7 initiates a program of immunologic defense against invading microbes through the concerted recruitment of multiple cytokines and chemokines. These results illustrate a novel potential mechanism of antimicrobial control that does not require the triggering of a full T-cell activation program and that the body may implement under conditions of lymphopenia in an attempt to reconstitute the lost immune function as well as to facilitate non-cytolytic immune-mediated suppression of HIV-1.