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: 10915934
• 负责人: paolo lusso
• 金额: $ 72.42万
• 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/10915934
• 关键词: Anatomy; Animals; Binding; CCL3 gene; CCL4 gene; Cells; Complex; Disease; Evaluation; Female; Gene Expression; Genes; Goals; HIV; HIV-1; Homeostasis; Homing; IL7 gene; Immune; Immune response; Immune system; Immunologic Receptors; Immunologics; In Vitro; Infection; Integrins; Interferon alpha; Intestines; Invaded; Knowledge; Ligands; Lymphocyte; Lymphopenia; Macaca; Macaca mulatta; Mediating; Microbe; Modeling; Molecular Cloning; P-selectin ligand protein; Pathogenesis; Patients; Phase; Prevention; RANTES; Readiness; Research; Role; Route; SIV; Signal Transduction; T-Cell Activation; T-Lymphocyte; TNF gene; Vagina; Viral; Virion; Virulence Factors; Virus Diseases; Work; antagonist; antimicrobial; chemokine; cytokine; immune function; immune modulating agents; immunoregulation; in vivo; integrin alpha4beta7; monocyte; mouse model; mucosal addressin cell adhesion molecule-1; novel; particle; pathogen; programs; receptor; reconstitution; recruit; simian human immunodeficiency virus; transcriptome sequencing; 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. 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.

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。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，从而将非T细胞重定向到肠道，而肠道是HIV-1复制的主要解剖部位。此外，我们发现a4b7在HIV-1病毒粒子从受感染细胞排出时被整合到病毒粒子中。在小鼠模型中，病毒颗粒结合的a4b7具有功能活性，因为它能够结合其天然配体MAdCAM-1，并促进HIV-1病毒颗粒的肠道归巢。重要的是，a4b7掺入也发生在hiv感染患者和siv感染的猕猴体内，这表明它可能是促进和维持肠道间室HIV-1感染的关键毒力因子，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/CD162)，在体外和体内都被纳入HIV-1病毒粒子。我们已经开始在猕猴模型中研究含有合并a4b7的SIV病毒颗粒是否具有增强的介导病毒传播的能力。因此，在含有或不含有a4b7的情况下，制备了SIVmac239的均匀分子克隆，并用于雌性猕猴阴道途径的传播研究。初步结果表明，合并a4b7的存在可能促进感染，即使在不同的猕猴中传播是高度不同的，正如对近亲繁殖动物的研究所预期的那样。进一步的研究正在进行中，以评估a4b7掺入对SIV经直肠内途径传播的优势是否更为显著。

项目成果

Sialic acid-binding Ig-like lectin-7 interacts with HIV-1 gp120 and facilitates infection of CD4pos T cells and macrophages.

• DOI: 10.1186/1742-4690-10-154
• 发表时间: 2013-12-13
• 期刊: Retrovirology
• 影响因子: 3.3
• 作者: Varchetta S;Lusso P;Hudspeth K;Mikulak J;Mele D;Paolucci S;Cimbro R;Malnati M;Riva A;Maserati R;Mondelli MU;Mavilio D
• 通讯作者: Mavilio D

The CD8-derived chemokine XCL1/lymphotactin is a conformation-dependent, broad-spectrum inhibitor of HIV-1.

• DOI: 10.1371/journal.ppat.1003852
• 发表时间: 2013
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Guzzo C;Fox J;Lin Y;Miao H;Cimbro R;Volkman BF;Fauci AS;Lusso P
• 通讯作者: Lusso P

Biological and physical characterization of the X4 HIV-1 suppressive factor secreted by LPS-stimulated human macrophages.

LPS 刺激的人类巨噬细胞分泌的 X4 HIV-1 抑制因子的生物学和物理特征。

• DOI: 10.1016/j.virol.2009.04.005
• 发表时间: 2009
• 期刊: Virology
• 影响因子: 3.7
• 作者: Mikulak,Joanna;Gianolini,Monica;Versmisse,Pierre;Pancino,Gianfranco;Lusso,Paolo;Verani,Alessia
• 通讯作者: Verani,Alessia

Inhibition of HIV-1 infection by human α-defensin-5, a natural antimicrobial peptide expressed in the genital and intestinal mucosae.

• DOI: 10.1371/journal.pone.0045208
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Furci L;Tolazzi M;Sironi F;Vassena L;Lusso P
• 通讯作者: Lusso P

P-selectin glycoprotein ligand-1 (PSGL-1/CD162) is incorporated into clinical HIV-1 isolates and can mediate virus capture and subsequent transfer to permissive cells.

• DOI: 10.1186/s12977-022-00593-5
• 发表时间: 2022-05-21
• 期刊: Retrovirology
• 影响因子: 3.3