HIV coreceptor downregulation as antiviral principle: SDF-1alpha-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication.
HIV coreceptor downregulation as antiviral principle: SDF-1alpha-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication.
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DOI：
10.1084/jem.186.1.139
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发表时间：
1997-07-07
影响因子：
15.3
通讯作者：
ArenzanaSeisdedos, F
中科院分区：
文献类型：
--
作者：
Amara, A;LeGall, S;Schwartz, O;Salamero, J;Montes, M;Loetscher, P;Baggiolini, M;Virelizier, JL;ArenzanaSeisdedos, F
CC趋化因子RANTES、MIP-1α或MIP-1β和CXC趋化因子SDF-1α分别连接CCR5和CXCR4，可显著抑制使用这些辅助受体进入T淋巴细胞的HIV毒株的复制。进入抑制的机制尚不清楚。我们发现SDF-1RANTES或其拮抗剂RANTES(9-68)可迅速而广泛地下调CXCR4和CCR5的表达。激光共聚焦扫描显微镜显示，CCR5和CXCR4与它们的配体结合后，被内化到囊泡中，与转铁蛋白受体共定位表明，这些囊泡符合早期内吞体内的条件。百日咳波氏杆菌毒素处理不影响内化，表明内化不依赖于Gi蛋白的信号传导。去除sdf-1α导致CXCR4CXCR4快速但不完全的表面重新表达，这一过程不被放线菌酮抑制，表明辅助受体正在从内化池中循环。CXCR4COOH末端胞质结构域的缺失不影响HIV进入，但可阻止SDF-1α诱导的受体下调，并降低SDF-1α作为HIV复制抑制因子的效力。我们的结果表明，辅助受体内化的能力不是HIV进入所必需的，但有助于CXC和CC趋化因子对HIV的抑制作用。
Ligation of CCR5 by the CC chemokines RANTES, MIP-1α or MIP-1β, and of CXCR4 by the CXC chemokine SDF-1α, profoundly inhibits the replication of HIV strains that use these coreceptors for entry into CD4+ T lymphocytes. The mechanism of entry inhibition is not known. We found a rapid and extensive downregulation of CXCR4 by SDF-1α and of CCR5 by RANTES or the antagonist RANTES(9-68). Confocal laser scanning microscopy showed that CCR5 and CXCR4, after binding to their ligands, are internalized into vesicles that qualify as early endosomes as indicated by colocalization with transferrin receptors. Internalization was not affected by treatment with Bordetella pertussis toxin, showing that it is independent of signaling via Gi-proteins. Removal of SDF-1α led to rapid, but incomplete surface reexpression of CXCR4, a process that was not inhibited by cycloheximide, suggesting that the coreceptor is recycling from the internalization pool. Deletion of the COOH-terminal, cytoplasmic domain of CXCR4 did not affect HIV entry, but prevented SDF-1α–induced receptor downregulation and decreased the potency of SDF-1α as inhibitor of HIV replication. Our results indicate that the ability of the coreceptor to internalize is not required for HIV entry, but contributes to the HIV suppressive effect of CXC and CC chemokines.
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