Role of the carbohydrate-binding sites of griffithsin in the prevention of DC-SIGN-mediated capture and transmission of HIV-1.
Role of the carbohydrate-binding sites of griffithsin in the prevention of DC-SIGN-mediated capture and transmission of HIV-1.
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DOI：
10.1371/journal.pone.0064132
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Balzarini J
中科院分区：
文献类型：
--
作者：
Hoorelbeke B;Xue J;LiWang PJ;Balzarini J
聚糖靶向C型DC-SIGN凝集素受体通过结合病毒并将捕获的HIV-1转移至CD 4 + T淋巴细胞而参与人类免疫缺陷病毒（HIV）的传播。碳水化合物结合剂（CBAs）已被报道阻断HIV-1感染。我们现在已经研究了有效的甘露糖特异性抗HIV CBA griffithsin（GRFT）抑制DC-SIGN捕获HIV-1的能力，其DC-SIGN定向传递到CD 4 + T淋巴细胞的能力以及GRFT的三个碳水化合物结合位点（CBS）在这些过程中的作用。GRFT抑制CEM的HIV-1（IIIB）感染和C8166 CD 4 + T淋巴细胞的HIV-1（NL4.3）感染，EC 50分别为0.059和0.444 nM。GRFT的单突变CBS变体（其中CBS之一中的关键Asp突变为Ala）在持续HIV-1感染的HuT-78和未感染的C8166 CD 4 + T淋巴细胞的共培养物中预防HIV-1感染的效力降低约20至60倍，抑制合胞体形成的效力降低约20至90倍。GRFT阻止DC-SIGN介导的病毒捕获和HIV-1传播至CD 4 + T淋巴细胞，EC 50分别为1.5 nM和0.012 nM。表面等离子体共振（SPR）的研究表明，野生型GRFT有效地阻止DC-SIGN和固定gp 120之间的结合，而点突变CBS变体的GRFT的效率低10- 15倍。SPR分析还表明，野生型GRFT及其单突变CBS变体具有以剂量依赖性方式从gp 120-DC-SIGN复合物中排出结合的gp 120的能力，这是HHA（另一种甘露糖特异性强效抗HIV-1 CBA）未观察到的特性。GRFT抑制HIV gp 120与DC-SIGN的结合，有效阻止DC-SIGN介导的HIV-1向CD 4 + T淋巴细胞的转移，并能够从gp 120-DC-SIGN复合物中排出gp 120。GRFT的功能完整的CBS对于GRFT的最佳作用是重要的。
The glycan-targeting C-type DC-SIGN lectin receptor is implicated in the transmission of the human immunodeficiency virus (HIV) by binding the virus and transferring the captured HIV-1 to CD4+ T lymphocytes. Carbohydrate binding agents (CBAs) have been reported to block HIV-1 infection. We have now investigated the potent mannose-specific anti-HIV CBA griffithsin (GRFT) on its ability to inhibit the capture of HIV-1 to DC-SIGN, its DC-SIGN-directed transmission to CD4+ T-lymphocytes and the role of the three carbohydrate-binding sites (CBS) of GRFT in these processes. GRFT inhibited HIV-1(IIIB) infection of CEM and HIV-1(NL4.3) infection of C8166 CD4+ T-lymphocytes at an EC50 of 0.059 and 0.444 nM, respectively. The single mutant CBS variants of GRFT (in which a key Asp in one of the CBS was mutated to Ala) were about ∼20 to 60-fold less potent to prevent HIV-1 infection and ∼20 to 90-fold less potent to inhibit syncytia formation in co-cultures of persistently HIV-1 infected HuT-78 and uninfected C8166 CD4+ T-lymphocytes. GRFT prevents DC-SIGN-mediated virus capture and HIV-1 transmission to CD4+ T-lymphocytes at an EC50 of 1.5 nM and 0.012 nM, respectively. Surface plasmon resonance (SPR) studies revealed that wild-type GRFT efficiently blocked the binding between DC-SIGN and immobilized gp120, whereas the point mutant CBS variants of GRFT were ∼10- to 15-fold less efficient. SPR-analysis also demonstrated that wild-type GRFT and its single mutant CBS variants have the capacity to expel bound gp120 from the gp120-DC-SIGN complex in a dose dependent manner, a property that was not observed for HHA, another mannose-specific potent anti-HIV-1 CBA. GRFT is inhibitory against HIV gp120 binding to DC-SIGN, efficiently prevents DC-SIGN-mediated transfer of HIV-1 to CD4+ T-lymphocytes and is able to expel gp120 from the gp120-DC-SIGN complex. Functionally intact CBS of GRFT are important for the optimal action of GRFT.
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影响因子：
64.5
作者：
Geijtenbeek, TBH;Torensma, R;Figdor, CG
通讯作者：
Figdor, CG
影响因子：
15
作者：
Belardi, Brian;O'Donoghue, Geoff P.;Smith, Adam W.;Groves, Jay T.;Bertozzi, Carolyn R.
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Schols, D
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