Hiv Coreceptor Downregulation as Antiviral Principle: Sdf-1 ␣ –dependent Internalization of the Chemokine Receptor Cxcr4 Contributes to Inhibition of Hiv Replication
Hiv Coreceptor Downregulation as Antiviral Principle: Sdf-1 ␣ –dependent Internalization of the Chemokine Receptor Cxcr4 Contributes to Inhibition of Hiv Replication
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A. Amara;S. Le Gall;Olivier Schwartz;Jean Salamero;Monica Montes;P. Loetscher;Marco Baggiolini;J. Virelizier;F. Arenzana‐Seisdedos;A. Amara;S. Le Gall
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作者：
A. Amara;S. Le Gall;Olivier Schwartz;Jean Salamero;Monica Montes;P. Loetscher;Marco Baggiolini;J. Virelizier;F. Arenzana‐Seisdedos;A. Amara;S. Le Gall
CC趋化因子RANTES、MIP-1␣或MIP-1和CXC趋化因子SDF-1␣连接CCR5和CXCR4，可显著抑制使用这些辅助受体进入CD_4ϩT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，表明内化不依赖于通过G-I蛋白传递的信号。去除sdf-1␣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端胞质结构域的缺失不影响HIV进入，但可阻止SDF-1␣诱导的受体下调，并降低SDF-1␣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。HIV(1，2)对人类细胞的生产性感染是必需的，但不是充分条件。几年前就假设存在一个额外的识别位点(3-4)，最近的研究表明，一些趋化因子受体实现了这一功能(5-10)。CXCR4和CCR5是主要的HIV辅助受体(5-7，10)，尽管CCR2b和CCR3(8，9)也有类似的功能。研究表明，CC趋化因子RANTES、MIP-1␣和MIP-1是CCR5的激动剂，它们可以抑制在感染早期优先分离的原代非合体诱导株的进入(11)。CXC趋化因子，SDF-1␣，CXCR4的配体，抑制细胞融合和被通常在疾病后期症状阶段分离的合胞体诱导(SI)型艾滋病毒株的感染(12，13)。趋化因子通过七个跨膜区受体与异源三聚体G I-蛋白偶联发挥作用。它们的抗病毒活性被认为依赖于竞争HIV包膜糖蛋白gp120与趋化因子受体(14，15)的结合。据报道，仅占用…
Ligation of CCR5 by the CC chemokines RANTES, MIP-1 ␣ or MIP-1  , and of CXCR4 by the CXC chemokine SDF-1 ␣ , profoundly inhibits the replication of HIV strains that use these coreceptors for entry into CD4 ϩ T lymphocytes. The mechanism of entry inhibition is not known. We found a rapid and extensive downregulation of CXCR4 by SDF-1 ␣ 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. Inter-nalization was not affected by treatment with Bordetella pertussis toxin, showing that it is independent of signaling via G i-proteins. Removal of SDF-1 ␣ 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, cy-toplasmic domain of CXCR4 did not affect HIV entry, but prevented SDF-1 ␣ –induced receptor downregulation and decreased the potency of SDF-1 ␣ 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. E xpression of CD4 is necessary but not sufficient for productive infection of human cells with HIV (1, 2). The existence of an additional recognition site was postulated several years ago (3–4), and it was recently shown that some chemokine receptors fulfill such a function (5–10). CXCR4 and CCR5 are the major HIV coreceptors (5–7, 10), although similar functions were also reported for CCR2b and CCR3 (8, 9). It has been shown that the CC chemokines, RANTES, MIP-1 ␣ , and MIP-1  , which are agonists for CCR5, inhibit entry of primary, non-syncy-tium–inducing (NSI) strains that are preferentially isolated at early stages of the infection (11). The CXC chemokine, SDF-1 ␣ , the ligand of CXCR4, inhibits cell fusion and infection by HIV strains of the syncytium-inducing (SI) phenotype that are usually isolated at late, symptomatic stages of the disease (12, 13). Chemokines act via seven-transmembrane domain receptors that couple to heterotrimeric G i-proteins. Their anti-viral activity is thought to depend on competition for the binding of the HIV envelope (Env) glycoprotein gp120 to chemokines receptors (14, 15). It has been reported that mere occupancy …