Férir Geoffrey, Huskens Dana, Noppen Sam, Koharudin Leonardus M I, Gronenborn Angela M, Schols Dominique
Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
J Antimicrob Chemother. 2014 Oct;69(10):2746-58. doi: 10.1093/jac/dku220. Epub 2014 Jun 25.
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.
Various cellular assays were used to determine antiviral activity against wild-type and certain CBA-resistant 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.
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 Manα(1-2)Man-specific 2G12 monoclonal antibody (mAb) as shown by flow cytometry and surface plasmon resonance analysis. The HIV-1 NL4.3(2G12res), NL4.3(MVNres) and IIIB(GRFTres) strains were equally inhibited as the wild-type HIV-1 strains by these CBAs. Combination studies indicate that OAA and OPA act synergistically with Hippeastrum hybrid agglutinin, 2G12 mAb and griffithsin (GRFT), with the exception of OPA/GRFT.
OAA and OPA are unique CBAs with broad-spectrum anti-HIV activity; however, further optimization will be necessary for microbicidal application.
颤藻凝集素同源物（OAAH）蛋白属于最近发现的凝集素家族。该家族的创始成员OAA以及设计的杂交体OAAH（OPA），与其他抗病毒碳水化合物结合剂（CBA）相比，识别相似但独特的Man-9碳水化合物结构。对这两种新描述的CBA进行了评估，以确定它们对HIV复制和传播的灭活特性以及作为杀微生物剂的潜力。
使用各种细胞试验来确定对野生型和某些CBA抗性HIV-1毒株的抗病毒活性：（i）在人T淋巴瘤细胞系和外周血单核细胞（PBMC）中进行游离HIV病毒体感染；（ii）使用持续感染HIV的T细胞和未感染的CD4+T细胞进行合胞体形成试验；（iii）DC-SIGN介导的病毒捕获；以及（iv）向未感染的CD4+T细胞的传播。还使用其他CBA评估了OAA和OPA的促有丝分裂特性和潜在的协同作用。
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捕获以及向CD4+靶T细胞的传播，从而使多种HIV-1和HIV-2临床分离株失去感染性，且与它们对共受体的使用无关。流式细胞术和表面等离子体共振分析表明，这两种CBA均竞争性抑制Manα(1-2)Man特异性2G12单克隆抗体（mAb）的结合。这些CBA对HIV-1 NL4.3(2G12res)、NL4.3(MVNres)和IIIB(GRFTres)毒株的抑制作用与野生型HIV-1毒株相同。联合研究表明，OAA和OPA与朱顶红凝集素、2G12 mAb和格里菲斯素（GRFT）协同作用，但OPA/GRFT组合除外。
OAA和OPA是具有广谱抗HIV活性的独特CBA；然而，杀微生物应用还需要进一步优化。
