Chemokines and some chemical analogs of chemokines prevent cellular HIV-1 entry when bound to the HIV-1 coreceptors C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4), which are G protein–coupled receptors (GPCRs). The ideal HIV-1 entry blocker targeting the coreceptors would display ligand bias and avoid activating G protein–mediated pathways that lead to inflammation. We compared CCR5-dependent activation of second messenger pathways in a single cell line. We studied two endogenous chemokines [RANTES (also known as CCL5) and MIP-1α (also known as CCL3)] and four chemokine analogs of RANTES (5P12-, 5P14-, 6P4-, and PSC-RANTES). We found that CCR5 signaled through both G_i/o and G_q/11. IP₁ accumulation and Ca²⁺ flux arose from G_q/11 activation, rather than from Gβγ subunit release after G_i/o activation as had been previously proposed. The 6P4- and PSC-RANTES analogs were superagonists for G_q/11 activation, whereas the 5P12- and 5P14-RANTES analogs displayed a signaling bias for G_i/o. These results demonstrate that RANTES analogs elicit G protein subtype–specific signaling bias and can cause CCR5 to couple preferentially to G_q/11 rather than to G_i/o signaling pathways. We propose that G protein subtype–specific signaling bias may be a general feature of GPCRs that can couple to more than one G protein family.

当趋化因子和某些趋化因子的化学类似物与HIV-1共同受体CC趋化因子受体5（CCR5）或CXC趋化因子受体4（CXCR4）结合时，它们阻止细胞中的HIV-1进入，这是G蛋白偶联受体（GPCR）。靶向共受体的理想HIV-1进入阻滞剂将显示配体偏倚，并避免激活导致炎症的G蛋白介导的途径。我们比较了单个细胞系中第二信使途径的CCR5依赖性激活。我们研究了两种内源性趋化因子[RANTES（也称为CCL5）和MIP-1α（也称为CCL3）]和RANTES的四种趋化因子类似物（5P12-，5P14-，6P4-和PSC-RANTES）。我们发现，CCR5通过G _{i / o}和G _{q / 11}发出信号。IP ₁累积和Ca ²⁺通量是由G _{q / 11}活化引起的，而不是由G _{i / o}活化后释放的Gβγ亚基引起的。6P4-和PSC-RANTES类似物是G _{q / 11}激活的超激动剂，而5P12-和5P14-RANTES类似物则显示G _{i / o}的信号偏向。这些结果表明，RANTES类似物会引起G蛋白亚型特异性信号转导偏倚，并可能导致CCR5优先与G _{q / 11}而非G _{i / o}信号通路偶联。我们认为，G蛋白亚型特异性信号偏倚可能是GPCR的一个普遍特征，它可以与多个G蛋白家族偶联。