Studies in a Murine Model Confirm the Safety of Griffithsin and Advocate Its Further Development as a Microbicide Targeting HIV-1 and Other Enveloped Viruses.
Studies in a Murine Model Confirm the Safety of Griffithsin and Advocate Its Further Development as a Microbicide Targeting HIV-1 and Other Enveloped Viruses.
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DOI：
10.3390/v8110311
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发表时间：
2016-11-17
期刊：
影响因子：
--
通讯作者：
Palmer KE
中科院分区：
文献类型：
--
作者：
Kouokam JC;Lasnik AB;Palmer KE
格里菲辛(GRFT)是格里菲斯属植物中的一种凝集素，在亚纳摩尔浓度下抑制人类免疫缺陷病毒-1(HIV-1)的复制，细胞毒性有限。然而，GRFT在体内的安全性尚不完全清楚，尤其是在静脉给药后。我们首先用流式细胞术评价了GRFT对小鼠外周血单个核细胞(MPBMC)活力、有丝分裂原和激活的影响，并用酶联免疫吸附试验(ELISA法)评价了GRFT对细胞因子分泌的影响。BALB/c小鼠单次皮下注射GRFT 50 mg/kg或每日14次10 mg/kg，观察GRFT的毒理学特性。在杀菌剂开发的背景下，分别在皮下、阴道和腹膜内给药后，测定了2 mg/kg的GRFT的毒性。有趣的是，GRFT没有引起mPBMCs的显著细胞死亡、有丝分裂、激活或细胞因子释放，验证了小鼠模型的有效性。GRFT在体内获得了良好的安全性：没有观察到动物体能、血液化学或CBC参数的明显变化。在GRFT治疗后，观察到可逆性的脾肿大，某些脾B和T细胞被激活。然而，GRFT(无论是单次高剂量还是慢性剂量)对脾组织均无病理改变。最后，2 mg/kg的GRFT经粘膜或全身治疗后未发现可检测到的毒性，应进一步开发为预防HIV的杀微生物剂。
Griffithsin (GRFT), a lectin from Griffithsia species, inhibits human immunodeficiency virus-1 (HIV-1) replication at sub-nanomolar concentrations, with limited cellular toxicity. However, in vivo safety of GRFT is not fully understood, especially following parenteral administration. We first assessed GRFT’s effects in vitro, on mouse peripheral blood mononuclear cell (mPBMC) viability, mitogenicity, and activation using flow-cytometry, as well as cytokine secretion through enzyme-linked immunosorbent assay (ELISA). Toxicological properties of GRFT were determined after a single subcutaneous administration of 50 mg/kg or 14 daily doses of 10 mg/kg in BALB/c mice. In the context of microbicide development, toxicity of GRFT at 2 mg/kg was determined after subcutaneous, intravaginal, and intraperitoneal administrations, respectively. Interestingly, GRFT caused no significant cell death, mitogenicity, activation, or cytokine release in mPBMCs, validating the usefulness of a mouse model. An excellent safety profile for GRFT was obtained in vivo: no overt changes were observed in animal fitness, blood chemistry or CBC parameters. Following GRFT treatment, reversible splenomegaly was observed with activation of certain spleen B and T cells. However, spleen tissues were not pathologically altered by GRFT (either with a single high dose or chronic doses). Finally, no detectable toxicity was found after mucosal or systemic treatment with 2 mg/kg GRFT, which should be further developed as a microbicide for HIV prevention.
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