TYROSINE-SULFATED PEPTIDE DERIVED FROM HIV-1 ANTIBODY INHIBITS HIV-1 INFECTION

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 HIV-1主要辅助受体CCR 5氨基末端的硫酸化酪氨酸在其结合HIV-1包膜糖蛋白gp 120和介导HIV- 1进入的能力中起关键作用。识别gp 120的CCR 5结合区的人抗体也通过酪氨酸硫酸化修饰，这是它们中和HIV-1的能力所必需的。在这里，我们证明，来自这些抗体之一，E51的CDR 3区的硫酸化肽，可以有效地结合gp 120。该肽pE 51与gp 120的结合需要酪氨酸硫酸化，并且通过CD 4增强，但不依赖于CD 4。四个pE 51酪氨酸中任一个的改变，或gp 120残基420、421或422的改变与CCR 5相关的关键防止gp 120与pE 51结合。pE 51比基于CCR 5氨基末端的肽更有效地中和HIV-1，并且可以用作与HIV-1进入的其它蛋白质抑制剂的融合伴侣。我们的数据提供了进一步的洞察到协会的CCR 5氨基末端与gp 120，显示一个保守的，硫酸盐结合区的gp 120是可访问的抑制剂在没有CD 4，并建议CCR 5的可溶性模拟物可以比以前认识到的更有效。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Sulfated tyrosines at the amino terminus of the principal HIV-1 coreceptor CCR5 play acritical role in its ability to bind the HIV-1 envelope glycoprotein gp120 and mediate HIV- 1 entry. Human antibodies that recognize the CCR5-binding region of gp120 are also modified by tyrosine sulfation, which is necessary for their ability to neutralize HIV-1. Here we demonstrate that a sulfated peptide derived from the CDR3 region of one of these antibodies, E51, can efficiently bind gp120. Association of this peptide, pE51, with gp120 requires tyrosine sulfation, and is enhanced by, but not dependent on, CD4. Alteration of any of four pE51 tyrosines, or alteration of gp120residues 420, 421, or 422critical for association with CCR5prevents gp120 association with pE51. pE51 neutralizes HIV-1 more effectively than peptides based on the CCR5 amino terminus, and may be useful as a fusion partner with other protein inhibitors of HIV-1 entry. Our data provide further insight into the association of the CCR5 amino terminus with gp120, show that a conserved, sulfate-binding region of gp120 is accessible to inhibitors in the absence of CD4, and suggest that soluble mimetics of CCR5 can be more effective than previously appreciated.