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: 10248096
• 负责人: paolo lusso
• 金额: $ 61.59万
• 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/10248096
• 关键词: Affect; Anatomy; Animals; Antibodies; Antiviral Agents; Apoptotic; 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; Immune; In Vitro; Infection; Integrins; Interleukin-7; 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 Diseases; Work; chemokine; cytokine; immune function; immunoregulation; in vivo; integrin alpha4beta7; intravenous administration; monocyte; mouse model; mucosal addressin cell adhesion molecule-1; novel; particle; prevent; programs; receptor; reconstitution; 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 principal 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 can 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, and this effect requires an active 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. Preliminary results point to a key role of TNF-a in the induction of anti-HIV chemokine by IL-7. These results illustrate a novel potential mechanism of HIV-1 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，在淋巴细胞减少（淋巴细胞损失）发生时，对于重建正常的t淋巴细胞池至关重要。此外，我们之前的工作表明，IL-7是主要肠道归巢整合素alpha4beta7 （a4b7）的有效诱导剂，它可能作为HIV-1的额外细胞受体，并在HIV-1疾病的发病机制中成为关键分子。事实上，肠道及其相关淋巴组织（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细胞的大量耗竭。体内研究进一步证实了a4b7在HIV-1感染中的作用，这些研究记录了抗a4b7抗体在感染猴免疫缺陷病毒（SIV）的猕猴中具有保护作用。经静脉注射一种引物抗a4b7单克隆抗体（mAb） ACT-1，可预防或延缓经反复低剂量阴道接种的猕猴SIV感染。