Groot Fedde, Sanders Rogier W, ter Brake Olivier, Nazmi Kamran, Veerman Enno C I, Bolscher Jan G M, Berkhout Ben
Department of Human Retrovirology, Academic Medical Center, Meibergdreef 15, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
J Virol. 2006 Sep;80(18):9236-43. doi: 10.1128/JVI.00796-06.
Antimicrobial peptides are found in a number of body compartments and are secreted at mucosal surfaces, where they form part of the innate immune system. Many of these small peptides have a broad spectrum of inhibitory activity against bacteria, fungi, parasites, and viruses. Generally, the peptide's mode of action is binding and disruption of membranes due to its amphipathic properties. Histatin 5 is a salivary peptide that inhibits Candida albicans, an opportunistic fungus that causes oropharyngeal candidiasis in a majority of human immunodeficiency virus type 1 (HIV-1)-infected patients progressing towards AIDS. Previously, we increased the fungicidal properties of histatin 5 by replacing amino acids in the active domain of histatin 5 (Dh-5) (A. L. Ruissen, J. Groenink, E. J. Helmerhorst, E. Walgreen-Weterings, W. van't Hof, E. C. Veerman, and A. V. Nieuw Amerongen, Biochem. J. 356:361-368, 2001). In the current study, we tested the anti-HIV-1 activity of Dh-5 and its derivatives. Although Dh-5 inhibited HIV-1 replication, none of the peptide variants were more effective in this respect. In contrast, one of the derivatives, Dhvar2, significantly increased HIV-1 replication by promoting the envelope-mediated cell entry process. Most likely, Dhvar2 affects membranes, thereby facilitating fusion of viral and cellular membranes. This study shows that modification of antimicrobial peptides in order to improve their activity against a pathogen may have unpredictable and unwanted side effects on other pathogens.
抗菌肽存在于许多身体腔室中，并在黏膜表面分泌，在那里它们构成先天免疫系统的一部分。这些小肽中的许多对细菌、真菌、寄生虫和病毒具有广泛的抑制活性。一般来说，由于其两亲性，该肽的作用方式是结合并破坏细胞膜。组蛋白5是一种唾液肽，可抑制白色念珠菌，这种机会性真菌在大多数进展为艾滋病的1型人类免疫缺陷病毒（HIV-1）感染患者中会引起口腔念珠菌病。此前，我们通过替换组蛋白5（Dh-5）活性域中的氨基酸来增强组蛋白5的杀真菌特性（A. L. Ruissen、J. Groenink、E. J. Helmerhorst、E. Walgreen-Weterings、W. van't Hof、E. C. Veerman和A. V. Nieuw Amerongen，《生物化学杂志》356:361-368，2001年）。在当前的研究中，我们测试了Dh-5及其衍生物的抗HIV-1活性。尽管Dh-5抑制了HIV-1复制，但在这方面没有一种肽变体更有效。相反，其中一种衍生物Dhvar2通过促进包膜介导的细胞进入过程显著增加了HIV-1复制。最有可能的是，Dhvar2影响细胞膜，从而促进病毒膜与细胞膜的融合。这项研究表明，为提高抗菌肽对病原体的活性而进行的修饰可能会对其他病原体产生不可预测且有害的副作用。
