Cd4+ Binding Proteins As Immunosuppression Factors

Cd4 结合蛋白作为免疫抑制因子

• 批准号: 6535267
• 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/6535267
• 关键词: AIDS vaccines; CD4 molecule; HIV envelope protein gp120; HIV infections; apoptosis; binding proteins; helper T lymphocyte; human immunodeficiency virus; human tissue; immunosuppression; interleukin 2; intermolecular interaction; microorganism culture; microorganism immunology; oral pharyngeal neoplasm; receptor binding; recombinant proteins; virus receptors

It appears that there is a conformation change in the C4 domain of HIV gp120 that allows gp120 to evade a neutralizing immune response and which may contribute to the toxicity of gp120. We synthesized peptides 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 immunological properties. When the C4 peptomer having an alpha helical conformation is used as the immunogen in monkeys, antibodies are formed that react with the parent gp120 and the antibodies block gp120 binding to CD4 but they do not inhibit HIV infection in vitro. Monkeys that were immunized with the peptomer had a very pronounced T helper cell response but, surprisingly, showed increased viremia following intrarectal challenge with live SIV. It thus appears that in monkeys C4 is contributing to SIV disease progression. 9 out of 10 human sera that were HIV+ contain antibodies that react with the C4 peptomer in the helical conformation but 3 out of 10 had antibodies that reacted with C4 in the cyclic conformation. In addition, 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 but they do not block gp120 binding to CD4. In addition, these antibodies magnify the toxic effects of gp120 on T cell production of IL-2, probably by crosslinking CD4 on the T cell surface. Affinity purified human anti cyclic C4 antibodies also augmented IL-2 attenuation by gp120. In summary, natural HIV infection causes the production of antibodies against the linear, helical and/or cyclic C4 peptide but, the antibodies appear to be harmful to the HIV+ host. Thus, even though the C4 domain of gp120 is highly conserved, it contributes to HIV pathogenesis by avoiding neutralizing immune responses The end result represents another way HIV protects itself from destruction by the immune system. The work clearly signals immune responses against C4 as being harmful and studies of future vaccine formulations should carefully focus in part on the harmful roles played by C4 if the C4 domain is a component of the vaccine.

HIV gp120 的 C4 结构域似乎存在构象变化，使得 gp120 能够逃避中和免疫反应，并可能导致 gp120 的毒性。我们从 gp120 的 C4 结构域合成了 2 种形式的肽；螺旋状和环状。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 CD4 的能力，但具有截然不同的免疫学特性。当具有α螺旋构象的C4肽聚体用作猴子的免疫原时，形成与亲本gp120反应的抗体，并且该抗体阻断gp120与CD4的结合，但它们在体外不抑制HIV感染。用 peptomer 免疫的猴子具有非常明显的 T 辅助细胞反应，但令人惊讶的是，在直肠内用活 SIV 攻击后，显示出病毒血症增加。因此，在猴子中，C4 似乎促进了 SIV 疾病的进展。 10 份 HIV+ 人类血清中，有 9 份含有与螺旋构象 C4 肽聚体反应的抗体，但十分之三含有与环状构象 C4 反应的抗体。此外，今年我们了解到，当环状C4肽用作兔子的免疫原时，会形成与亲本gp120反应的抗体，但它们不会阻止gp120与CD4的结合。此外，这些抗体可能通过在 T 细胞表面交联 CD4 来放大 gp120 对 T 细胞产生 IL-2 的毒性作用。亲和纯化的人抗环 C4 抗体也增强了 gp120 对 IL-2 的减弱作用。总之，自然HIV感染导致产生针对线性、螺旋和/或环状C4肽的抗体，但是这些抗体似乎对HIV+宿主有害。因此，尽管 gp120 的 C4 结构域高度保守，但它通过避免中和免疫反应而促进 HIV 发病机制。最终结果代表了 HIV 保护自身免受免疫系统破坏的另一种方式。这项工作清楚地表明针对 C4 的免疫反应是有害的，如果 C4 结构域是疫苗的一个组成部分，那么未来疫苗配方的研究应仔细关注 C4 所发挥的有害作用。