Activity of and Effect of Subcutaneous Treatment with the Broad-Spectrum Antiviral Lectin Griffithsin in Two Laboratory Rodent Models
Activity of and Effect of Subcutaneous Treatment with the Broad-Spectrum Antiviral Lectin Griffithsin in Two Laboratory Rodent Models
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DOI：
10.1128/aac.01407-13
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发表时间：
2014-01-01
影响因子：
4.9
通讯作者：
Palmer, Kenneth E.
中科院分区：
文献类型：
--
作者：
Barton, Christopher;Kouokam, J. Calvin;Palmer, Kenneth E.
Griffithsin（GRFT）是一种红细胞来源的凝集素，可结合人类免疫缺陷病毒1型（HIV-1）、HIV-2和其他包膜病毒（包括丙型肝炎病毒（HCV）、严重急性呼吸道综合征冠状病毒（SARS-CoV）和埃博拉病毒）表面上发现的N-连接聚糖的末端甘露糖残基。GRFT不显示人T细胞促有丝分裂活性，并且在处理的人细胞系中不诱导促炎细胞因子的产生。然而，尽管越来越多的证据显示GRFT具有广谱纳摩尔或更好的抗病毒活性，但没有研究报告GRFT作为潜在的全身抗病毒治疗的安全性的全面评估。本研究中给出的结果表明，在两种啮齿动物种属中，GRFT的一系列单次和重复每日皮下给药诱导的毒性最小，尽管我们注意到脾脏和肝脏质量的给药相关增加，表明存在抗药免疫应答。该药物全身分布，皮下给药后在血清和血浆中蓄积至高水平。此外，我们表明，GRFT治疗的动物血清保留抗HIV-1包膜假病毒在基于细胞的中和试验中的抗病毒活性。总体而言，我们在此提供的数据表明，GRFT累积至耐受性最低且毒性最小的相关治疗浓度。这些研究支持GRFT作为针对包膜病毒的全身性抗病毒治疗剂的进一步开发，尽管如果将其用于慢性病毒感染的长期治疗，则可能需要使该分子去免疫化。
Griffithsin (GRFT) is a red-alga-derived lectin that binds the terminal mannose residues of N-linked glycans found on the surface of human immunodeficiency virus type 1 (HIV-1), HIV-2, and other enveloped viruses, including hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Ebola virus. GRFT displays no human T-cell mitogenic activity and does not induce production of proinflammatory cytokines in treated human cell lines. However, despite the growing evidence showing the broad-spectrum nanomolar or better antiviral activity of GRFT, no study has reported a comprehensive assessment of GRFT safety as a potential systemic antiviral treatment. The results presented in this work show that minimal toxicity was induced by a range of single and repeated daily subcutaneous doses of GRFT in two rodent species, although we noted treatment-associated increases in spleen and liver mass suggestive of an antidrug immune response. The drug is systemically distributed, accumulating to high levels in the serum and plasma after subcutaneous delivery. Further, we showed that serum from GRFT-treated animals retained antiviral activity against HIV-1-enveloped pseudoviruses in a cell-based neutralization assay. Overall, our data presented here show that GRFT accumulates to relevant therapeutic concentrations which are tolerated with minimal toxicity. These studies support further development of GRFT as a systemic antiviral therapeutic agent against enveloped viruses, although deimmunizing the molecule may be necessary if it is to be used in long-term treatment of chronic viral infections.