Broad anti-HIV activity of the Oscillatoria agardhii agglutinin homologue lectin family
Broad anti-HIV activity of the Oscillatoria agardhii agglutinin homologue lectin family
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DOI：
10.1093/jac/dku220
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发表时间：
2014-10-01
影响因子：
5.2
通讯作者：
Schols, Dominique
中科院分区：
文献类型：
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作者：
Ferir, Geoffrey;Huskens, Dana;Schols, Dominique
目的：阿氏颤藻凝集素同源蛋白（OAAH）属于新近发现的凝集素家族。与其他抗病毒碳水化合物结合剂（CBAs）相比，创始成员OAA和设计的杂合OAAH（OPA）识别Man-9的相似但独特的碳水化合物结构。这两个新描述的CBAs被评价为它们对HIV复制和传播的灭活特性以及它们作为杀微生物剂的潜力。方法：使用各种细胞测定来确定对野生型和某些CBAs抗性HIV-1株的抗病毒活性：（i）在人T淋巴瘤细胞系和PBMC中的游离HIV病毒体感染;（ii）使用持续HIV感染的T细胞和未感染的CD 4（+）T细胞的合胞体形成测定;（iii）DC-SIGN介导的病毒捕获;和（iv）向未感染的CD 4（+）T细胞的传播。结果：OAA和OPA抑制HIV复制、HIV-1感染和未感染T细胞之间的合胞体形成、DC-SIGN介导的HIV-1捕获和向CD 4（+）靶T细胞的传播，从而使多种HIV-1和HIV-2临床分离株不具有感染性，而与其辅助受体的使用无关。如流式细胞术和表面等离子体共振分析所示，两种CBA竞争性抑制Mana（1-2）Man特异性2G 12单克隆抗体（mAb）的结合。这些CBA对HIV-1 NL4.32G12res、NL4.3MVNres和IIIBGRFTres株的抑制作用与野生型HIV-1株相同。OAA和OPA与朱顶红杂交凝集素、2G 12 mAb和griffithsin（GRFT）具有协同作用，但OPA/GRFT.Conclusions：OAA和OPA是具有广谱抗HIV活性的独特CBAs;
Objectives: Oscillatoria agardhii agglutinin homologue (OAAH) proteins belong to a recently discovered lectin family. The founding member OAA and a designed hybrid OAAH (OPA) recognize similar but unique carbohydrate structures of Man-9, compared with other antiviral carbohydrate-binding agents (CBAs). These two newly described CBAs were evaluated for their inactivating properties on HIV replication and transmission and for their potential as microbicides.Methods: Various cellular assays were used to determine antiviral activity against wild-type and certain CBAresistant HIV-1 strains: (i) free HIV virion infection in human T lymphoma cell lines and PBMCs; (ii) syncytium formation assay using persistently HIV-infected T cells and non-infected CD4(+) T cells; (iii) DC-SIGN-mediated viral capture; and (iv) transmission to uninfected CD4(+) T cells. OAA and OPA were also evaluated for their mitogenic properties and potential synergistic effects using other CBAs.Results: OAA and OPA inhibit HIV replication, syncytium formation between HIV-1-infected and uninfected T cells, DC-SIGN-mediated HIV-1 capture and transmission to CD4(+) target T cells, thereby rendering a variety of HIV-1 and HIV-2 clinical isolates non-infectious, independent of their coreceptor use. Both CBAs competitively inhibit the binding of the Mana(1-2) Man-specific 2G12 monoclonal antibody (mAb) as shown by flow cytometry and surface plasmon resonance analysis. The HIV-1 NL4.32G12res, NL4.3MVNres and IIIBGRFTres strains were equally inhibited as the wild-type HIV-1 strains by these CBAs. Combination studies indicate that OAA and OPA act synergistically with Hippeastrumhybrid agglutinin, 2G12mAb and griffithsin (GRFT), with the exception of OPA/GRFT.Conclusions: OAA and OPA are unique CBAs with broad-spectrum anti-HIV activity; however, further optimization will be necessary for microbicidal application.