Casoli Claudio, Pilotti Elisabetta, Perno Carlo Federico, Balestra Emanuela, Polverini Eugenia, Cassone Antonio, Conti Stefania, Magliani Walter, Polonelli Luciano
Department of Clinical Medicine, Nephrology and Health Sciences, University of Parma, Viale Antonio Gramsci 14, 43100 Parma, Italy.
AIDS. 2006 Apr 24;20(7):975-80. doi: 10.1097/01.aids.0000222068.14878.0d.
To verify whether a synthetic therapeutic killer decapeptide (KP), a functional mimotope of a yeast killer toxin with wide-spectrum microbicidal activity, inclusive of AIDS-related opportunistic micro-organisms, through interaction with beta-glucan receptors, which has been found to possess sequence homology with critical segments in gp160 V1/V2 and V3 loops, may also be inhibiting HIV-1 replication.
Primary peripheral blood mononuclear cells (PBMCs) cultures established from HIV-1-infected patients were treated with KP in comparison with zidovudine and supernatants and cells were harvested for analysis of HIV RNA and proviral contents, respectively. Virus production in exogenous in-vitro PBMCs infection with lymphocytotropic and monocytotropic HIV-1 strains was also assessed in presence of KP by enzyme-linked immunosorbent assay HIV p24 gag antigen detection. The binding affinity of KP to CD4, CCR5 and CXCR4 was evaluated on CD4-CCR5 or CD4-CXCR4 transfected astroglioma cell lines.
KP was shown to be devoid of cytotoxicity on PBMCs and to inhibit HIV-1 replication in PBMCs of a patient in the acute phase of infection. The antiretroviral activity of KP, which proved to be more potent than zidovudine at micromolar concentrations, is abolished by beta 1,3-glucan but not by beta 1,6-glucan. Down-regulation of CCR5 co-receptor, and/or physical block of the gp120-receptor interaction are possible mechanisms of KP activity.
KP appears to be the first antibody-derived short peptide displaying an inhibitory activity against HIV-1 and related opportunistic micro-organisms by different mechanisms of action.
验证一种合成治疗性杀伤十肽（KP），一种具有广谱杀菌活性的酵母杀伤毒素的功能性模拟表位，包括与艾滋病相关的机会性微生物，通过与β-葡聚糖受体相互作用，已发现其与gp160 V1/V2和V3环中的关键片段具有序列同源性，是否也能抑制HIV-1复制。
将从HIV-1感染患者建立的原代外周血单核细胞（PBMC）培养物与齐多夫定一起用KP处理，分别收集上清液和细胞用于分析HIV RNA和前病毒含量。还通过酶联免疫吸附测定HIV p24 gag抗原检测，在存在KP的情况下评估淋巴细胞嗜性和单核细胞嗜性HIV-1毒株对外源体外PBMC感染的病毒产生。在CD4-CCR5或CD4-CXCR4转染的星形胶质瘤细胞系上评估KP对CD4、CCR5和CXCR4的结合亲和力。
显示KP对PBMC无细胞毒性，并能抑制感染急性期患者PBMC中的HIV-1复制。KP的抗逆转录病毒活性在微摩尔浓度下比齐多夫定更有效，被β1,3-葡聚糖消除，但不被β1,6-葡聚糖消除。CCR5共受体的下调和/或gp120受体相互作用的物理阻断可能是KP活性的机制。
KP似乎是第一种源自抗体的短肽，通过不同的作用机制对HIV-1和相关机会性微生物显示出抑制活性。
