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gp120介导病毒颗粒进入CD4+T细胞。Gp120与CD4受体和辅助受体CCR5或CXCR4结合。这些受体表达在人类淋巴细胞和巨噬细胞的一部分上，因此正是这些细胞有效地感染了艾滋病毒。由于gp120是唯一能引发中和抗体的病毒蛋白，它是旨在阻止艾滋病毒感染人类细胞的治疗药物的主要靶点，也是潜在艾滋病疫苗的关键成分。Gp120也被C型凝集素受体和其他尚未识别的受体识别。我们最近发现整合素a4b7是CD4+T细胞表面的一种额外的HIV-1受体。Alpha4beta7受体是淋巴细胞归巢到肠道相关淋巴组织(GALT)固有层的主要整合素，而HIV的主要靶点是定位于淋巴组织中的CD4+T细胞，尤其是GALT。我们的观察表明，HIV gp120和Alpha4beta7之间的直接相互作用为在GALT中优先建立和/或维持HIV复制提供了一个可信的机制解释。Gp120与α4beta7的结合是由其V2环中的LDV肽序列介导的，该序列重申了MadCAM-1、VCAM-1和纤维连接蛋白上存在的结构上同源的结合基序，这些都是α4beta7的天然配体。去除HIV包膜中的该序列会取消与α4beta7整合素的结合。基于LDV序列的原型α4β7肽拮抗剂可抑制gp120与α4β7整合素的结合。这表明目前正在临床开发的许多α4整合素拮抗剂也将抑制这种相互作用。我们目前的工作集中在α4beta7整合素在HIV复制、传播和致病机制中的作用。