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。此外，我们以前的工作表明，IL-7是一个有效的诱导剂的主要肠道归巢整合素，α 4 β 7（a4 b7），这可能是一个额外的细胞受体的HIV-1，并正在成为一个关键的分子在HIV-1疾病的发病机制。事实上，肠道及其相关的淋巴组织（GALT）构成了HIV-1复制的主要解剖部位，特别是在HIV感染的早期阶段，导致CD 4 + T细胞的大量耗竭。体内研究进一步证实了a4 b7在HIV-1感染中的作用，这些研究记录了抗a4 b7抗体在感染猿猴免疫缺陷病毒（SIV）的猕猴中的保护作用。静脉注射灵长类抗-a4 b7单克隆抗体（mAb），ACT-1，发现预防或延迟SIV感染的猕猴反复低剂量阴道接种的挑战。 HIV-1有能力将一系列宿主细胞蛋白质整合到其外部包膜中，这可能影响其细胞向性和感染性。几年前，我们发现a4 b7是HIV-1最有效整合的宿主蛋白之一。病毒体掺入的整联蛋白具有功能活性，因为它能够与其天然配体MAdCAM-1结合，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。在过去的一年中，我们已经开始调查是否SIV病毒粒子包含纳入a4 b7有能力增加介导的猕猴模型中的病毒传播。因此，SIV mac 239的单个分子克隆在重组系统中被产生为具有或不具有并入的a4 b7，并且在体外广泛的感染性滴定后用于猕猴传播研究。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。传播后感染过程的详细特征正在进行中。 关于IL-7，我们已经研究了这种细胞因子是否可以诱导CCR 5结合趋化因子的产生，即，RANTES/CCL 5、MIP-1a/CCL 3和MIP-1b/CCL 4是HIV-1感染的天然拮抗剂。我们发现，IL-7，在超稳态浓度和在没有任何伴随的刺激，是一种有效的诱导剂抗HIV趋化因子以及其他细胞因子参与抗菌免疫反应，这种效果需要一个积极的和接触依赖性的T细胞和单核细胞之间的串扰。目前正在深入研究介导这种细胞间串扰的机制以及所涉及的细胞相关和可溶性因子。我们也在研究TNF-α在IL-7诱导抗HIV趋化因子中的关键作用，以及IFN活性的辅助因子。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细胞内病原体，如病毒，通过协调招聘的多种细胞因子和趋化因子。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. Moreover, our previous work demonstrated that IL-7 is a potent inducer of the main gut-homing integrin, alpha4beta7 (a4b7), which may serve as an additional cellular receptor for HIV-1 and is emerging as a critical molecule in the pathogenesis of HIV-1 disease. Indeed, the gut and its associated lymphoid tissue (GALT) constitute a primary anatomical site for HIV-1 replication, particularly during the early stages of HIV infection, leading to extensive depletion of CD4+ T cells. The role of a4b7 in HIV-1 infection is further corroborated by in vivo studies that documented a protective role of anti-a4b7 antibodies in macaques infected with simian immunodeficiency virus (SIV). Intravenous administration of a primatized anti-a4b7 monoclonal antibody (mAb), ACT-1, was found to prevent or delay SIV infection in macaques challenged by repeated low-dose vaginal inoculation. HIV-1 has the capacity to incorporate a range of host-cell proteins into its external envelope, which may affect its cellular tropism and infectivity. A few years ago, we found that a4b7 was one of the host proteins most efficiently incorporated by HIV-1. The virion-incorporated integrin 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. Over the past year, 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 single molecular clone of SIV mac239 was produced either with or without incorporated a4b7 in a recombinant system and used for macaque transmission studies after extensive infectivity titration in vitro. 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. A detailed characterization of the infection course after transmission in ongoing. With regard to IL-7, we have investigated whether this cytokine can induce the production of CCR5-binding chemokines, i.e., RANTES/CCL5, MIP-1a/CCL3 and MIP-1b/CCL4, which act as natural antagonists of HIV-1 infection. We found that IL-7, at suprahomeostatic concentrations and in the absence of any concomitant stimulation, is a potent inducer of anti-HIV chemokines as well as other cytokines involved in antimicrobial immune responses, and this effect requires an active and contact-dependent cross-talk between T cells and monocytes. An in-depth characterization of the mechanisms that mediate this intercellular cross-talk and the cell-associated and soluble factors involved is under way. We are also investigating the key role of TNF-a in the induction of anti-HIV chemokines by IL-7, as well as a cofactor for IFN activities. Overall, our results demonstrate that IL-7 initiates a program of immunologic defense against intracellular pathogens, like viruses, by 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.