The Potent Anti-HIV Activity of CXCL12γ Correlates with Efficient CXCR4 Binding and Internalization
The Potent Anti-HIV Activity of CXCL12γ Correlates with Efficient CXCR4 Binding and Internalization
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DOI：
10.1128/jvi.00342-09
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发表时间：
2010-03-01
影响因子：
5.4
通讯作者：
Alkhatib, Ghalib
中科院分区：
文献类型：
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作者：
Altenburg, Jeffrey D.;Jin, Qingwen;Alkhatib, Ghalib
我们先前证明，天然存在的剪接变体基质细胞衍生因子1 γ/CXCL 1 γ是阻断X4 HIV-1的最有效的CXCL 12同种型，具有弱的趋化活性。在CXCL 12的所有六种同种型中发现了位于N末端的保守BBX B结构域（B表示碱性，X表示任何残基）（（KHLK 27）-K-24）。为了确定CXCL 12 γ的有效抗病毒活性是否是由于额外C末端BBXB结构域的存在，我们单独以及组合地突变每个结构域。尽管CXCL 12 γ与硫酸乙酰肝素蛋白聚糖（HSPG）的结合比CXCL 12 α所观察到的高10倍，但结果并未证明HSPG结合与有效的抗病毒活性之间的直接相关性。缺乏保守BBXB结构域的CXCL 12 γ突变体（命名为γ B1）显示出与HSPG的结合增加，但抗HIV活性降低。相反，缺乏C-末端第二和/或第三BBXB结构域但保留保守结构域（命名为B2、B3和B23）的突变体显示出与HSPG的结合降低，但抗HIV活性增加。B2、B3和B23突变体与增强的CXCR 4结合、受体内化和恢复的趋化性相关。CXCR 4的内化在CXCL 12 γ中比在CXCL 12 α中更有效，并且当保守的BBXB结构域突变时显著降低。我们得出结论，观察到的CXCL 12 γ的有效抗HIV-1活性是由于对CXCR 4的亲和力增加和有效的受体内化。
We previously demonstrated that the naturally occurring splice variant stromal cell-derived factor 1 gamma/CXCL1 gamma is the most potent CXCL12 isoform in blocking X4 HIV-1, with weak chemotactic activity. A conserved BBXB domain (B for basic and X for any residue) located in the N terminus ((KHLK27)-K-24) is found in all six isoforms of CXCL12. To determine whether the potent antiviral activity of CXCL12 gamma is due to the presence of the extra C-terminal BBXB domains, we mutated each domain individually as well as in combination. Although binding of CXCL12 gamma to heparan sulfate proteoglycan (HSPG) was 10-fold higher than that observed with CXCL12 alpha, the results did not demonstrate a direct correlation between HSPG binding and the potent antiviral activity. CXCL12 gamma mutants lacking the conserved BBXB domain (designated gamma B1) showed increased binding to HSPG but reduced anti-HIV activity. In contrast, the mutants lacking the C-terminal second and/or third BBXB domain but retaining the conserved domain (designated B2, B3, and B23) showed decreased binding to HSPG but increased anti-HIV activity. The B2, B3, and B23 mutants were associated with enhanced CXCR4 binding, receptor internalization, and restored chemotaxis. Internalization of CXCR4 was more potent with CXCL12 gamma than with CXCL12 alpha and was significantly reduced when the conserved BBXB domain was mutated. We concluded that the observed potent anti-HIV-1 activity of CXCL12 gamma is due to increased affinity for CXCR4 and to efficient receptor internalization.