CD4+ binding proteins as immunosuppression factors

似乎HIV gp120的C4结构域存在构象变化，使gp120逃避中和免疫反应，这可能是导致gp120毒性的原因之一。我们从gp120的C4结构域合成了两种形式的多肽：螺旋和环状。我们了解到，尽管这两种形式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学特性。当具有α螺旋构象的C4肽被用作猴子的免疫原时，会形成与亲本gp120反应的抗体，但抗体不会阻止gp120与CD4的结合，也不会在体外抑制HIV感染。用胃肠肽免疫的猴子有非常显著的T辅助细胞反应，但令人惊讶的是，在用活的SIV直肠内攻击后，显示出更多的病毒血症。因此，在猴子中，C4似乎促进了SIV疾病的进展。在10份HIV阳性的人血清中，有9份含有与螺旋构象中的C4肽链反应的抗体，但10份中有3份含有与环状构象中的C4反应的抗体。此外，今年我们了解到，当环状C4肽被用作兔的免疫原时，会形成抗体，与亲本gp120发生反应，但它们不会阻止gp120与CD4的结合。此外，这些抗体放大了gp120对T细胞产生IL-2的毒性作用，可能是通过使T细胞表面的CD4交联而实现的。亲和纯化的人抗循环C4抗体也能增强gp120对IL-2的抑制作用。总之，自然感染HIV会导致产生抗线性、螺旋和/或环状C4多肽的抗体，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促进了HIV的发病。最终结果代表了HIV保护自己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，未来疫苗配方的研究应该谨慎地部分集中在C4所起的有害作用上，如果C4结构域是疫苗的一个组成部分。

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 but the antibodies do not block gp120 binding to CD4 and 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.