Cationic polypeptides are required for anti-HIV-1 activity of human vaginal fluid
Cationic polypeptides are required for anti-HIV-1 activity of human vaginal fluid
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DOI：
10.4049/jimmunol.175.11.7560
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Cole, AM
中科院分区：
文献类型：
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作者：
Venkataraman, N;Cole, AL;Cole, AM
阴道粘膜表面是HIV-1异性传播的门户，因此在原发感染的发病机制中起着重要作用。在寻找人类阴道液在先天宿主防御中的作用的直接生物学证据时，我们表征了最小操作的阴道液内的阳离子多肽的抗HIV-1功能。在目前的研究中，我们发现，阴道液赋予固有的抗HIV-1特性，对X4和R5株的HIV-1，可以防止HIV-1感染，并减少前病毒基因组整合在人体宫颈阴道组织的器官型培养。该活性的大部分包含在阳离子多肽级分中，并且使用选择性阳离子交换树脂消耗阳离子多肽消除了大部分针对HIV-1的固有活性。通过将阳离子多肽级分加入到耗尽的阴道液中，我们能够恢复抗HIV-1的活性。使用蛋白质组学的方法，我们确定了18个阳离子多肽阴道液，几乎所有这些都是已知的抗菌剂或在宿主防御中具有其他据称的作用。有趣的是，生理浓度的13种阳离子多肽单独对HIV-1没有活性，但在一起，它们部分恢复了阳离子耗尽的阴道液的抗HIV-1活性。这些结果表明，阳离子多肽之间的协同作用是复杂的，并且完全抗HIV-1活性可能涉及阳离子肽和蛋白质在阴道液中的聚集。
Mucosal surfaces of the vagina are the portals for heterosexual transmission of HIV-1 and therefore play a fundamental role in the pathogenesis of primary infection. In the search for direct biological evidence for the role of human vaginal fluid in innate host defense, we characterized the anti-HIV-1 function of cationic polypeptides within minimally manipulated vaginal fluid. In the current study we revealed that vaginal fluid confers intrinsic anti-HIV-1 properties against both X4 and R5 strains of HIV-1 and could protect against HIV-1 infection and reduce proviral genome integration in organotypic cultures of human cervicovaginal tissue. The majority of this activity was contained in the cationic polypeptide fraction, and the depletion of cationic polypeptides using a selective cation exchange resin ablated most of the intrinsic activity against HIV-1. By adding the cationic polypeptide fraction to depleted vaginal fluid, we were able to restore activity against HIV-1. Using a proteomic approach, we identified 18 cationic polypeptides within vaginal fluid, nearly all of which are either known antimicrobials or have other purported roles in host defense. Interestingly, physiologic concentrations of 13 of the cationic polypeptides were not active alone against HIV-1, yet in concert they partially restored the anti-HIV-1 activity of cation-depleted vaginal fluid. These results suggest that synergism between cationic polypeptides is complex, and full anti-HIV-1 activity probably involves the aggregate of the cationic peptides and proteins in vaginal fluid.