CD4+ BINDING PROTEINS AS IMMUNOSUPPRESSION FACTORS

CD4 结合蛋白作为免疫抑制因子

• 批准号: 6289671
• 负责人: Frank A. Robey
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 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/6289671
• 关键词: CD4 molecule; CD40 molecule; HIV envelope protein gp120; HIV infections; T cell receptor; apoptosis; athymic mouse; gel electrophoresis; helper T lymphocyte; human tissue; immunologic assay /test; immunosuppression; neoplasm /cancer immunology; neoplasm /cancer transplantation; receptor binding; recombinant proteins; xenotransplantation

A conformational change in C4 of gp120 fools the immune response against HIV. We synthesized a peptide from the C4 domain of gp120 in 2 forms – helical and cyclic. We learned that both forms, although having the same amino acid sequence and ability to bind recombinant soluble CD4, have very different biological and immunological properties. When the C4 peptomer having an alpha helical conformation is used as the immunogen in rabbits, antibodies are formed that react with the parent gp120 but the antibodies do not block gp120 binding to CD4 and they do not inhibit HIV infection in vitro. Rabbit anti C4 peptomer antibodies did not block the gp120 attenuation of IL-2 production by Jurkat cells in response to conconavalin A. 9 out of 10 human sera that were HIV+ do contain antibodies that react with the C4 peptomer in the helical conformation. This year we learned that, when the cyclic C4 peptide is used as an immunogen in rabbits, antibodies are formed that react with the parent gp120 and these antibodies do block gp120 binding to CD4 and they do inhibit HIV infection in vitro. Anti cyclic C4 antibodies decreased the amount that gp120 attenuates IL-2 production by Jurkat cells responding to conconavalin A. Only 1 out of 10 HIV+ human sera that were tested contained antibodies that reacted with the C4 cyclized peptide. In summary, natural HIV infection causes the production of antibodies against the linear and/or helical C4 peptide but, in order to be protective, the antibodies should be against the cyclic or looped conformation of C4. Thus, a conformation shift from loop to helix by C4 allows gp120 to dodge a neutralizing immune response. By avoiding immune surveillance this way, gp120 can bind to cell surface CD4 without being blocked by antibodies. The end result represents another way HIV protects itself from destruction by the immune system. The C4 peptide in the cyclized form now is being developed as an immunogen to be included in future HIV vaccine formulations and as an immunotherapeutic to provide neutralizing anti C4 antibodies to HIV+ individuals who are lacking these specific antibodies. - CD4, immunosuppression, gp120, HIV, vaccine, T cells, oral cancer, IL-2, peptides, conformation

gp 120的C4构象变化欺骗了针对HIV的免疫应答。我们从gp 120的C4结构域合成了两种形式的螺旋和环状肽。我们了解到，这两种形式虽然具有相同的氨基酸序列和结合重组可溶性CD 4的能力，但具有非常不同的生物学和免疫学特性。当将具有α螺旋构象的C4肽异构体用作兔的免疫原时，形成与亲本gp 120反应的抗体，但该抗体不阻断gp 120与CD 4的结合，并且它们在体外不抑制HIV感染。兔抗C4肽聚体抗体并不能阻断gp 120对Jurkat细胞响应刀豆球蛋白A产生IL-2的减弱。10份HIV+的人血清中有9份含有与螺旋构象的C4肽异构体反应的抗体。今年我们了解到，当环C4肽被用作兔子的免疫原时，会形成与亲本gp 120反应的抗体，这些抗体确实会阻断gp 120与CD 4的结合，并且它们确实会抑制体外HIV感染。抗环C4抗体降低了gp 120减弱Jurkat细胞对伴球蛋白A产生IL-2的量。10份HIV阳性人血清中只有1份含有与C4环化肽反应的抗体。总之，天然HIV感染导致产生针对线性和/或螺旋C4肽的抗体，但是为了具有保护性，抗体应该针对C4的环状或环状构象。因此，通过C4从环到螺旋的构象转变允许gp 120躲避中和免疫应答。通过这种方式避免免疫监视，gp 120可以与细胞表面CD 4结合而不被抗体阻断。最终的结果代表了艾滋病毒保护自己免受免疫系统破坏的另一种方式。环化形式的C4肽目前正在开发作为免疫原，包括在未来的HIV疫苗制剂中，并作为免疫调节剂，为缺乏这些特异性抗体的HIV+个体提供中和抗C4抗体。- 免疫抑制，gp 120，HIV，疫苗，T细胞，口腔癌，IL-2，多肽，构象