Inhibition of HIV-1 infection by human α-defensin-5, a natural antimicrobial peptide expressed in the genital and intestinal mucosae.
Inhibition of HIV-1 infection by human α-defensin-5, a natural antimicrobial peptide expressed in the genital and intestinal mucosae.
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DOI：
10.1371/journal.pone.0045208
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lusso P
中科院分区：
文献类型：
--
作者：
Furci L;Tolazzi M;Sironi F;Vassena L;Lusso P
α-defensin-5 (HD5) 是先天免疫系统的关键效应物，具有广泛的抗菌和抗病毒活性。生殖器和胃肠道粘膜中有专门的上皮细胞分泌 HD5，这两个解剖部位与 HIV-1 传播和发病机制密切相关。我们之前发现，人中性粒细胞防御素 (HNP)-1 和 -2 通过与病毒包膜及其主要细胞受体 CD4 的特异性双边相互作用来抑制 HIV-1 进入。尽管氨基酸同一性较低，但人防御素 5 (HD5) 与 HNP 具有高度的结构同源性。在这里，我们证明，在类似于粘膜液中的无血清和低离子强度条件下，HD5 以低微摩尔浓度抑制原代 CD4+ T 淋巴细胞的 HIV-1 感染。在原代毒株和实验室适应毒株中均观察到对 HIV-1 感染的阻断，并且与病毒辅助受体使用表型无关。与 HNP 类似，HD5 通过干扰外膜糖蛋白、gp120 和 CD4 之间的相互作用来抑制 HIV-1 进入靶细胞。在高浓度下，HD5 还被发现下调 CXCR4 辅助受体的表达，但不下调 CCR5 的表达。与其广谱活性一致，抗体竞争研究表明，HD5 与 gp120 的 CD4 和辅助受体结合位点重叠的区域结合，但不与 V3 环区域结合，该区域包含辅助受体使用特异性的主要决定因素。这些发现为粘膜水平上针对 HIV-1 的第一道免疫防御提供了新的见解，并为预防和治疗策略的制定开辟了新的视角。
α-defensin-5 (HD5) is a key effector of the innate immune system with broad anti-bacterial and anti-viral activities. Specialized epithelial cells secrete HD5 in the genital and gastrointestinal mucosae, two anatomical sites that are critically involved in HIV-1 transmission and pathogenesis. We previously found that human neutrophil defensins (HNP)-1 and -2 inhibit HIV-1 entry by specific bilateral interaction both with the viral envelope and with its primary cellular receptor, CD4. Despite low amino acid identity, human defensin-5 (HD5) shares with HNPs a high degree of structural homology. Here, we demonstrate that HD5 inhibits HIV-1 infection of primary CD4+ T lymphocytes at low micromolar concentration under serum-free and low-ionic-strength conditions similar to those occurring in mucosal fluids. Blockade of HIV-1 infection was observed with both primary and laboratory-adapted strains and was independent of the viral coreceptor-usage phenotype. Similar to HNPs, HD5 inhibits HIV-1 entry into the target cell by interfering with the reciprocal interaction between the external envelope glycoprotein, gp120, and CD4. At high concentrations, HD5 was also found to downmodulate expression of the CXCR4 coreceptor, but not of CCR5. Consistent with its broad spectrum of activity, antibody competition studies showed that HD5 binds to a region overlapping with the CD4- and coreceptor-binding sites of gp120, but not to the V3 loop region, which contains the major determinants of coreceptor-usage specificity. These findings provide new insights into the first line of immune defense against HIV-1 at the mucosal level and open new perspectives for the development of preventive and therapeutic strategies.
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影响因子：
3.4
作者：
Hickey, D. K.;Patel, M. V.;Fahey, J. V.;Wira, C. R.
通讯作者：
Wira, C. R.
DOI：
10.1111/j.1600-0897.2007.00561.x
发表时间：
2008-01-01
影响因子：
3.6
作者：
Cole, Alexander M.;Cole, Amy Liese
通讯作者：
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影响因子：
16.8
作者：
Appay, V;Rowland-Jones, SL
通讯作者：
Rowland-Jones, SL
DOI：
10.1126/science.1175868
发表时间：
2009-11-20
期刊：
Science (New York, N.Y.)
影响因子：
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Chen L;Kwon YD;Zhou T;Wu X;O'Dell S;Cavacini L;Hessell AJ;Pancera M;Tang M;Xu L;Yang ZY;Zhang MY;Arthos J;Burton DR;Dimitrov DS;Nabel GJ;Posner MR;Sodroski J;Wyatt R;Mascola JR;Kwong PD
通讯作者：
Kwong PD
影响因子：
3.4
作者：
Davis, HE;Rosinski, M;Yarmush, ML
通讯作者：
Yarmush, ML