α-Defensin HD5 Inhibits Human Papillomavirus 16 Infection via Capsid Stabilization and Redirection to the Lysosome.
α-Defensin HD5 Inhibits Human Papillomavirus 16 Infection via Capsid Stabilization and Redirection to the Lysosome.
复制标题
α-防御素HD5通过衣壳稳定和重定向抑制人乳头瘤病毒16感染。
DOI：
10.1128/mbio.02304-16
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发表时间：
2017-01-24
期刊：
影响因子：
6.4
通讯作者：
Smith JG
中科院分区：
文献类型：
--
作者：
Wiens ME;Smith JG
α-防御素是一类重要的丰富的先天免疫效应物，对许多非包膜病毒病原体具有有效的抗病毒作用；然而，缺乏一种共同的机制来解释它们阻断这些不相关病毒感染的能力。我们之前发现，人防御素5 （HD5）阻断了人乳头瘤病毒（HPV）感染所需的一个关键宿主介导的蛋白水解加工步骤。在这里，我们发现绕过这种切割的要求不能消除HD5的抑制作用。相反，HD5改变了HPV在细胞中的运输。在HD5抑制浓度存在的情况下，HPV被内化并到达早期内体。内化的衣壳对抗体和蛋白酶具有渗透性；然而，HD5阻止了病毒衣壳与基因组的分离，减少了病毒向反式高尔基网络的运输，将传入的病毒颗粒重定向到溶酶体，并加速了内化衣壳蛋白的降解。这一机制与HD5抑制人腺病毒的机制相同。因此，我们的数据支持在感染期间衣壳稳定和重定向到溶酶体是α-防御素对抗非包膜病毒的一般抗病毒机制。尽管α-防御素对包膜病毒的抗病毒活性在很大程度上可以通过干扰受体结合和融合来解释，但抑制非包膜病毒的共同机制仍不清楚。在对一种在肠道和男性和女性泌尿生殖道中表达的重要的人类α-防御素的研究中，我们发现了HPV和人类腺病毒感染抑制机制之间惊人的相似之处。因此，α-防御素对两种不同病毒细胞内转运影响的详细研究支持α-防御素对非包膜病毒抗病毒活性的一般机制。
α-Defensins are an important class of abundant innate immune effectors that are potently antiviral against a number of nonenveloped viral pathogens; however, a common mechanism to explain their ability to block infection by these unrelated viruses is lacking. We previously found that human defensin 5 (HD5) blocks a critical host-mediated proteolytic processing step required for human papillomavirus (HPV) infection. Here, we show that bypassing the requirement for this cleavage failed to abrogate HD5 inhibition. Instead, HD5 altered HPV trafficking in the cell. In the presence of an inhibitory concentration of HD5, HPV was internalized and reached the early endosome. The internalized capsid became permeable to antibodies and proteases; however, HD5 prevented dissociation of the viral capsid from the genome, reduced viral trafficking to the trans-Golgi network, redirected the incoming viral particle to the lysosome, and accelerated the degradation of internalized capsid proteins. This mechanism is equivalent to the mechanism by which HD5 inhibits human adenovirus. Thus, our data support capsid stabilization and redirection to the lysosome during infection as a general antiviral mechanism of α-defensins against nonenveloped viruses. Although the antiviral activity of α-defensins against enveloped viruses can be largely explained by interference with receptor binding and fusion, a common mechanism for inhibition of nonenveloped viruses remains elusive. In studies of a prominent human α-defensin that is expressed in the gut and in the male and female genitourinary tract, we discovered striking parallels between the mechanisms of inhibition of HPV and human adenovirus infection. Thus, detailed studies of the impact of α-defensins on the intracellular trafficking of two disparate viruses support a general mechanism of α-defensin antiviral activity against nonenveloped viruses.