Interaction of HIV envelope with cell surface receptors

HIV 包膜与细胞表面受体的相互作用

• 批准号: 7964440
• 负责人: Anthony S. Fauci
• 金额: $ 74.31万
• 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/7964440
• 关键词: AIDS Vaccines; B-Lymphocytes; Binding; Biochemical; C Type Lectin Receptors; CCR5 gene; CD4 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; CXCR4 gene; Cell Surface Receptors; Cells; Clinical; Dendritic Cells; Development; Disease; Excision; Exhibits; Genetic Variation; Goals; Gut associated lymphoid tissue; HIV; HIV Envelope Protein gp120; HIV envelope protein; HIV-1; Homing; Human; Immune; Infection; Integrin alpha4; Integrins; Lamina Propria; Ligands; Lymphocyte; Lymphoid Tissue; Maintenance; Mediating; Natural Killer Cells; Pathogenesis; Peptides; Reagent; Recombinants; Role; Surface; System; T-Lymphocyte; Therapeutic Agents; Vascular Cell Adhesion Molecule-1; Viral; Viral Proteins; Work; base; design; env Gene Products; integrin alpha4beta7; macrophage; neutralizing antibody; novel; particle; protein aminoacid sequence; receptor; transmission process

The HIV envelope protein, gp120, mediates entry of viral particles into CD4+ T cells. Gp120 binds to the CD4 receptor and a co-receptor, either CCR5 or CXCR4. These receptors are expressed on a subset of human lymphocytes and macrophages, and thus it is these cells that are productively infected by HIV. Because gp120 is the only viral protein against which neutralizing antibodies are elicited, it is a primary target of therapeutic agents designed to block infection of human cells by HIV, and a key component of a potential AIDS vaccine. Gp120 is also recognized by C-type lectin receptors, and other yet unidentified receptors. We have recently identified integrin a4b7 as an additional HIV-1 receptor on the surface of CD4+ T cells. The alpha4beta7 receptor is the principal integrin involved in lymphocyte homing to the lamina propria of gut-associated lymphoid tissue (GALT), and the primary targets of HIV are CD4+ T-cells localized to lymphoid tissues, particularly GALT. Our observations suggest that the direct interaction between HIV gp120 and alpha4beta7 provides a plausible mechanistic explanation for the preferential establishment and/or maintenance of HIV replication in GALT. Gp120-binding to alpha4beta7 is mediated by an LDV peptide sequence in its V2 loop that reiterates a structurally homologous binding motif present on MadCAM-1, VCAM-1 and fibronectin, which are the natural ligands for alpha4beta7. Removal of this sequence in the HIV envelope abrogates binding to alpha4beta7 integrin. A prototypical alpha4beta7 peptide antagonist based on the LDV sequence inhibits gp120 binding to alpha4beta7 integrin. This suggests that many of the alpha4 integrin antagonists that are currently in clinical development will also inhibit this interaction. Our current work is focused on the role of alpha4beta7 integrin in HIV replication, transmission and pathogenesis.

HIV包膜蛋白gp 120介导病毒颗粒进入CD 4 + T细胞。Gp 120与CD 4受体和辅助受体CCR 5或CXCR 4结合。这些受体在人类淋巴细胞和巨噬细胞的亚群上表达，因此正是这些细胞被HIV有效感染。由于gp 120是唯一的病毒蛋白质，针对其引发中和抗体，它是设计用于阻断HIV感染人类细胞的治疗剂的主要靶标，并且是潜在的AIDS疫苗的关键组分。Gp 120也被C型凝集素受体和其他尚未鉴定的受体识别。我们最近已经确定整合素a4 b7作为CD 4 + T细胞表面上的另外的HIV-1受体。α 4 β 7受体是参与淋巴细胞归巢至肠相关淋巴组织（GALT）固有层的主要整联蛋白，并且HIV的主要靶标是定位于淋巴组织（特别是GALT）的CD 4 + T细胞。我们的观察结果表明，HIV gp 120和α 4 β 7之间的直接相互作用提供了一个合理的机制解释的优先建立和/或维持HIV复制GALT。Gp 120与α 4 β 7的结合是由其V2环中的LDV肽序列介导的，该肽序列重申了存在于MadCAM-1、VCAM-1和纤连蛋白上的结构同源结合基序，MadCAM-1、VCAM-1和纤连蛋白是α 4 β 7的天然配体。去除HIV包膜中的该序列消除了与α 4 β 7整联蛋白的结合。基于LDV序列的原型α 4 β 7肽拮抗剂抑制gp 120与α 4 β 7整联蛋白的结合。这表明目前临床开发的许多α 4整联蛋白拮抗剂也将抑制这种相互作用。我们目前的工作集中在α 4 β 7整合素在HIV复制、传播和发病机制中的作用。