Protection Efficacy of C5A Against Vaginal and Rectal HIV Challenges in Humanized Mice.
Protection Efficacy of C5A Against Vaginal and Rectal HIV Challenges in Humanized Mice.
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DOI：
10.2174/1874357901812010001
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发表时间：
2018-01-01
期刊：
影响因子：
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通讯作者：
Moss, John A
中科院分区：
文献类型：
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作者：
Gallay, Philippe A;Chatterji, Udayan;Moss, John A
导言：在缺乏疫苗的情况下，迫切需要确定有效的药物，以防止艾滋病毒在未感染的个人中传播。非疫苗生物医学预防(NBP)方法，如局部或全身暴露前预防(PrEP)，是有希望减缓艾滋病传播的策略。方法：在本研究中，我们研究了病毒膜破坏两亲性SWLRDIWDWICEVLSDFK多肽C5a的杀菌效果。我们选择了骨髓/肝脏/胸腺(BLT)人源化小鼠模型作为经阴道和直肠传播HIV的模型。结果：外用C5a对人源化小鼠的阴道和直肠HIV攻击具有完全的保护作用。在证明C5a在人源化小鼠中阻止生殖器艾滋病毒传播后，我们检查了其杀菌性能的分子要求。我们发现，去除C5a两端的四个氨基酸并不会降低其杀菌效果。然而，去掉两端的四个氨基酸，就取消了它防止经阴道或直肠传播艾滋病毒的能力，这表明该肽的长度是C5a杀菌活性的关键参数。结论：C5a具有非细胞细胞毒活性，具有中和HSV和HIV的特性，其独特的作用机制破坏了病毒膜的稳定性，是一种有吸引力的多用途杀菌候选物质，可与包括抗逆转录病毒在内的其他抗HIV药物联合使用。
INTRODUCTION: In the absence of a vaccine, there is an urgent need for the identification of effective agents that prevent HIV transmission in uninfected individuals. Non-vaccine Biomedical Prevention (nBP) methods, such as topical or systemic pre-exposure prophylaxis (PrEP), are promising strategies to slow down the spread of AIDS.METHODS: In this study, we investigated the microbicidal efficacy of the viral membrane-disrupting amphipathic SWLRDIWDWICEVLSDFK peptide called C5A. We chose the bone marrow/liver/thymus (BLT) humanized mouse model as vaginal and rectal HIV transmission models.RESULTS: We found that the topical administration of C5A offers complete protection against vaginal and rectal HIV challenges in humanized mice. After demonstrating that C5A blocks genital HIV transmission in humanized mice, we examined the molecular requirements for its microbicidal property. We found that the removal of four amino acids on either end of C5A does not diminish its microbicidal efficacy. However, the removal of four amino acids at both the ends, abolishes its capacity to prevent vaginal or rectal HIV transmission, suggesting that the length of the peptide is a critical parameter for the microbicidal activity of C5A. Moreover, we demonstrated that the amphipathicity of the helical peptide as well as its hydrophobic surface represents key factors for the microbicidal activity of C5A in humanized mice.CONCLUSION: With its noncellular cytotoxic activity, its property of neutralizing both HSV and HIV, and its unique mechanism of action that disrupts the stability of the viral membrane, C5A represents an attractive multipurpose microbicidal candidate to be combined with other anti-HIV agents including antiretrovirals.