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CCR5或CXCR4的共受体结合。这些受体在人类淋巴细胞和巨噬细胞的一部分上表达，因此，这些细胞被HIV有效地感染。由于GP120是唯一引起中和抗体的病毒蛋白，因此它是旨在通过HIV阻断人类细胞感染的治疗剂的主要靶标，也是潜在AIDS疫苗的关键成分。 GP120也通过C型凝集素受体和其他未识别的受体认可。我们最近将整联蛋白A4B7鉴定为CD4+ T细胞表面上的附加HIV-1受体。 α4BETA7受体是参与与肠道相关淋巴组织（GALT）层淋巴细胞归巢的主要整合素，HIV的主要靶标是CD4+ T细胞局部局限于淋巴机构，尤其是GALT。我们的观察结果表明，HIV GP120与alpha4beta7之间的直接相互作用为GALT中HIV复制的优先建立和/或维持提供了合理的机械解释。 gp120绑定到alpha4beta7是由其V2环中的LDV肽序列介导的，该LDV肽序列重申存在于MadCAM-1，VCAM-1和Fibronectin上的结构同源结合基序，VCAM-1和Fibronectin上是Alpha4beta7的天然配体。在HIV包膜中的该序列去除该序列废除了与alpha4beta7整合素的结合。基于LDV序列的原型α4BETA7肽拮抗剂抑制GP120与alpha4beta7整合素的结合。这表明目前正在临床发育中的许多α4整联蛋白拮抗剂也会抑制这种相互作用。我们目前的工作集中在α4Beta7整合素在HIV复制，传播和发病机理中的作用上。