Cd4+ Binding Proteins As Immunosuppression Factors

Cd4 结合蛋白作为免疫抑制因子

• 批准号: 6673972
• 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/6673972
• 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.

似乎在HIV gp120的C4结构域中存在构象变化，使gp120能够逃避中和性免疫反应，这可能有助于gp120的毒性。我们从gp120的C4结构域合成了两种形式的肽；螺旋和循环。我们了解到，这两种形式，尽管具有相同的氨基酸序列和结合重组可溶性CD4的能力，但具有非常不同的免疫特性。当在猴子体内使用具有α螺旋构象的C4肽体作为免疫原时，形成抗体，与亲本gp120反应，抗体阻断gp120与CD4的结合，但它们在体外不抑制HIV感染。注射了这种酶的猴子有非常明显的辅助性T细胞反应，但令人惊讶的是，在用活SIV进行直肠内攻击后，猴子表现出了增加的病毒血症。因此，在猴子中，C4似乎有助于SIV疾病的进展。10个HIV阳性的人类血清中有9个含有与螺旋构象的C4肽体反应的抗体但10个中有3个抗体与环状构象的C4反应。此外，今年我们了解到，当环C4肽被用作兔的免疫原时，抗体会与亲本gp120发生反应，但它们不会阻止gp120与CD4的结合。此外，这些抗体可能通过T细胞表面的CD4交联，放大了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的衰减。综上所述，自然HIV感染导致产生针对线状、螺旋状和/或环状C4肽的抗体，但这些抗体似乎对HIV+宿主有害。因此，尽管gp120的C4结构域是高度保守的，但它通过避免中和免疫反应而参与HIV的发病机制，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，未来疫苗配方的研究应谨慎地部分关注C4发挥的有害作用。

项目成果

A defined conformational epitope from the C4 domain of HIV type 1 glycoprotein 120: anti-cyclic C4 antibodies from HIV-positive donors magnify glycoprotein 120 suppression of interleukin 2 produced by T cells.

来自 HIV 1 型糖蛋白 120 的 C4 结构域的明确构象表位：来自 HIV 阳性供体的抗环 C4 抗体可放大糖蛋白 120 对 T 细胞产生的白细胞介素 2 的抑制。

• DOI: 10.1089/08892220151126625
• 发表时间: 2001
• 期刊: AIDS research and human retroviruses
• 影响因子: 1.5
• 作者: Robey,FA;Robert-Guroff,M
• 通讯作者: Robert-Guroff,M

A conformational C4 peptide polymer vaccine coupled with live recombinant vector priming is immunogenic but does not protect against rectal SIV challenge.

构象 C4 肽聚合物疫苗与活重组载体引发相结合具有免疫原性，但不能防止直肠 SIV 攻击。

• DOI: 10.1089/088922201750252034
• 发表时间: 2001
• 期刊: AIDS research and human retroviruses
• 影响因子: 1.5
• 作者: Patterson,LJ;Robey,F;Muck,A;VanRemoortere,K;Aldrich,K;Richardson,E;Alvord,WG;Markham,PD;Cranage,M;Robert-Guroff,M
• 通讯作者: Robert-Guroff,M