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

IL-7 和整合素 α4β7 在人类免疫缺陷病毒感染中的作用

• 批准号: 10689598
• 负责人: paolo lusso
• 金额: $ 76.32万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689598
• 关键词: Affect; Anatomy; Animals; Antibodies; Binding; CCL3 gene; CCL4 gene; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Cellular Tropism; Disease; Dose; Evaluation; Goals; HIV; HIV Infections; HIV Receptors; HIV-1; Homeostasis; Homing; IL7 gene; Immune; Immune response; Immune system; Immunologic Receptors; Immunologics; Immunomodulators; In Vitro; Infection; Integrins; Interferons; Knowledge; Ligands; Lymphocyte; Lymphoid Tissue; Lymphopenia; Macaca; Macaca mulatta; Mediating; Modeling; Molecular Cloning; Monoclonal Antibodies; Pathogenesis; Patients; Phase; Prevention; Primates; Production; Proteins; RANTES; Recombinants; Research; Role; SIV; System; T-Cell Activation; T-Lymphocyte; TNF gene; Titrations; Vagina; Viral; Viral Pathogenesis; Virion; Virulence Factors; Virus; Virus Diseases; Work; antagonist; antimicrobial; chemokine; cofactor; cytokine; immune function; immunoregulation; in vivo; integrin alpha4beta7; intravenous administration; monocyte; mouse model; mucosal addressin cell adhesion molecule-1; novel; particle; pathogen; prevent; programs; receptor; reconstitution; recruit; simian human immunodeficiency virus; transmission process; viral transmission

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.

白细胞介素7(IL-7)是体内主要的T细胞稳态因子，在发生淋巴细胞减少(淋巴细胞丧失)时，对重建正常的T淋巴细胞库至关重要。此外，我们以前的工作表明，IL-7是主要的肠道归巢整合素α4β7(A4b7)的有效诱导剂，α4β7(A4b7)可能是HIV-1的额外细胞受体，并正在成为HIV-1疾病发病机制中的关键分子。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CD4+T细胞的广泛耗尽。体内研究进一步证实了a4b7在HIV-1感染中的作用，这些研究证明了抗a4b7抗体对感染猴免疫缺陷病毒(SIV)的猕猴具有保护作用。静脉注射抗a4b7单抗ACT-1可预防或延缓反复低剂量阴道接种的猕猴的SIV感染。 HIV-1具有将一系列宿主细胞蛋白结合到其外膜中的能力，这可能会影响其细胞趋向性和感染性。几年前，我们发现a4b7是HIV-1最有效地结合的宿主蛋白之一。整合了病毒粒子的整合素具有功能活性，因为它能够与其天然配体MAdCAM-1结合，并在小鼠模型中促进HIV-1病毒颗粒的肠道归巢。重要的是，在HIV感染患者和SIV感染的猕猴体内也存在a4b7掺入，这表明它可能是促进和维持肠道内HIV-1感染的一个关键毒力因子，特别是在HIV-1感染的早期阶段。在过去的一年里，我们已经开始研究含有A4b7的SIV病毒粒子在猕猴模型中是否具有更强的介导病毒传播的能力。因此，在重组系统中掺入或不掺入a4b7的SIV mac239的单分子克隆被用于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，结合了a4b7的存在可能会促进感染，尽管在不同的猕猴中传播是高度不同的，正如在对近交系动物的研究中所预期的那样。传播后感染过程的详细特征正在进行中。 关于IL-7，我们研究了这种细胞因子是否能诱导产生与CCR5结合的趋化因子，即RANTES/CCL5、MIP-1a/CCL3和MIP-1b/CCL4，这些趋化因子是HIV-1感染的天然拮抗剂。我们发现，在超稳态浓度和没有任何伴随刺激的情况下，IL-7是抗HIV趋化因子和其他参与抗微生物免疫反应的细胞因子的有效诱导剂，这一效应需要T细胞和单核细胞之间的活跃和接触依赖的串扰。对调节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素的深入描述正在进行中。我们还在研究肿瘤坏死因子-α在IL-7诱导抗HIV趋化因子中的关键作用，以及干扰素活性的辅助因素。总体而言，我们的结果表明，IL-7通过多种细胞因子和趋化因子的协同募集，启动了针对细胞内病原体(如病毒)的免疫防御计划。这些结果说明了一种新的潜在的抗微生物控制机制，该机制不需要触发完整的T细胞激活程序，并且身体可以在淋巴细胞减少的情况下实施，试图重建失去的免疫功能，以及促进非溶细胞性免疫介导的抑制HIV-1。