LD78β, a non-allelic variant of human MIP-1α (LD78α), has enhanced receptor interactions and potent HIV suppressive activity
LD78β, a non-allelic variant of human MIP-1α (LD78α), has enhanced receptor interactions and potent HIV suppressive activity
复制标题
DOI：
10.1074/jbc.274.25.17478
复制
发表时间：
1999-06-18
影响因子：
4.8
通讯作者：
Graham, GJ
中科院分区：
文献类型：
--
作者：
Nibbs, RJB;Yang, JY;Graham, GJ
趋化因子通过激活七螺旋G蛋白偶联受体在炎症和非炎症情况下发挥不同的作用。此外，许多趋化因子受体可以作为辅助因子的人免疫缺陷病毒（HIV）在体外进入细胞。CCR 5是趋化因子MLP-1 α（LD 78 α）、MIP-1 β、RAN-TES和MCP 2的受体，在体内特别重要，因为该基因的多态性影响HIV感染和进展为APDS的速率。此外，CCR 5配体可以阻止HIV通过该受体进入，并可能有助于控制HIV感染。在这里，我们表明，一个非等位基因亚型的人MIP-1 α（LD 78 α），称为LD 78 β或MIP-1 α P，具有增强的受体结合亲和力CCR 5（类似于6倍）和混杂的β-趋化因子受体，D 6（类似于15-20倍）。我们证明，在MIP-1 α P的位置2的脯氨酸残基是负责这种增强的活性。此外，MIP-1 α P是迄今为止所描述的最有效的天然CCR 5激动剂，重要的是，它显示出比所有其他检测的人MIP-1 α同种型明显更高的HIV 1抑制活性。此外，虽然RANTES被描述为CCR 5介导的HIV进入的最有效的抑制剂，但在HIV-1抑制测定中，MIP-1 α P与RANTES一样有效，如果不是更有效的话。这一特性表明，MLP-1 α P可能在控制HN感染个体中的病毒传播方面具有重要意义。
Chemokines play diverse roles in inflammatory and non-inflammatory situations via activation of heptahelical G-protein-coupled receptors. Also, many chemokine receptors can act as cofactors for cellular entry of human immunodeficiency virus (HIV) in vitro. CCR5, a receptor for chemokines MLP-1 alpha (LD78 alpha), MIP-1 beta, RAN-TES, and MCP2, is of particular importance in vivo as polymorphisms in this gene affect HIV infection and rate of progression to APDS. Moreover, the CCR5 ligands can prevent HIV entry through this receptor and likely contribute to the control of HIV infection. Here we show that a non-allelic isoform of human MIP-1 alpha (LD78 alpha), termed LD78 beta or MIP-1 alpha P, has enhanced receptor binding affinities to CCR5 (similar to 6-fold) and the promiscuous beta-chemokine receptor, D6 (similar to 15-20-fold). We demonstrate that a proline residue at position 2 of MIP-1 alpha P is responsible for this enhanced activity. Moreover, MIP-1 alpha P is by far the most potent natural CCR5 agonist described to date, and importantly, displays markedly higher HIV1 suppressive activity than all other human MIP-1 alpha isoforms examined. In addition, while RANTES has been described as the most potent inhibitor of CCR5-mediated HIV entry, MIP-1 alpha P was as potent as, if not more potent than, RANTES in HIV-1 suppressive assays. This property suggests that MLP-1 alpha P may be of importance in controlling Viral spread in HN-infected individuals.