Protection Efficacy of C5A Against Vaginal and Rectal HIV Challenges in Humanized Mice.

The Open Virology Journal Pub Date : 2018-02-28 eCollection Date: 2018-01-01 DOI:10.2174/1874357901812010001
Philippe A Gallay, Udayan Chatterji, Aaron Kirchhoff, Angel Gandarilla, Richard B Pyles, Marc M Baum, John A Moss
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Abstract

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.

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C5A 对人源化小鼠阴道和直肠艾滋病病毒挑战的保护效力
导言:在没有疫苗的情况下,迫切需要找到有效的药物来预防艾滋病毒在未感染者中的传播。非疫苗生物医学预防(nBP)方法,如局部或全身暴露前预防(PrEP),是减缓艾滋病传播的有希望的策略:在这项研究中,我们研究了名为 C5A 的病毒膜破坏性两亲性 SWLRDIWDWICEVLSDFK 肽的杀微生物功效。我们选择骨髓/肝脏/胸腺(BLT)人源化小鼠模型作为阴道和直肠传播艾滋病病毒的模型:结果:我们发现,在人源化小鼠的阴道和直肠艾滋病病毒挑战中,C5A 的局部给药可提供完全的保护。在证明 C5A 可阻断人源化小鼠生殖器艾滋病病毒传播后,我们研究了其杀微生物特性的分子要求。我们发现,去除 C5A 两端的四个氨基酸不会降低其杀菌功效。然而,去掉两端的四个氨基酸后,其防止阴道或直肠艾滋病病毒传播的能力就会消失,这表明肽的长度是 C5A 杀微生物活性的一个关键参数。此外,我们还证明了螺旋肽的两亲性及其疏水性表面是C5A在人源化小鼠体内发挥杀微生物活性的关键因素:C5A具有非细胞细胞毒性活性、同时中和HSV和HIV的特性以及破坏病毒膜稳定性的独特作用机制,是一种极具吸引力的多用途杀微生物候选药物,可与其他抗HIV药物(包括抗逆转录病毒药物)联合使用。
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