Roan Nadia R, Münch Jan, Arhel Nathalie, Mothes Walther, Neidleman Jason, Kobayashi Akiko, Smith-McCune Karen, Kirchhoff Frank, Greene Warner C
Gladstone Institute of Virology and Immunology, University of California, P.O. Box 419100, San Francisco, CA 94141-9100, USA.
J Virol. 2009 Jan;83(1):73-80. doi: 10.1128/JVI.01366-08. Epub 2008 Oct 22.
Human semen contains peptides capable of forming amyloid fibrils termed semen-derived enhancer of viral infection (SEVI) that can greatly increase human immunodeficiency virus (HIV) infection. While SEVI appears to enhance virion attachment to target cells, its underlying mechanism of action is unknown. We now demonstrate that the intrinsic positive charges of SEVI (pI = 10.21) facilitate virion attachment to and fusion with target cells. A mutant form of SEVI in which lysines and arginines are replaced with alanines retains the ability to form amyloid fibrils but is defective in binding virions and enhancing infection. In addition, the interaction of wild-type SEVI with virions and the ability of these fibrils to increase infection are abrogated in the presence of various polyanionic compounds. These anionic polymers also decrease the enhancement of HIV infection mediated by semen. These findings suggest that SEVI enhances viral infection by serving as a polycationic bridge that neutralizes the negative charge repulsion that exists between HIV virions and target cells. Combinations of agents that neutrale SEVI action and produce HIV virucidal effects are an attractive future direction for microbicide development.
人类精液中含有能够形成淀粉样纤维的肽，称为病毒感染精液衍生增强剂（SEVI），它能极大地增加人类免疫缺陷病毒（HIV）感染。虽然SEVI似乎能增强病毒粒子与靶细胞的附着，但其潜在作用机制尚不清楚。我们现在证明，SEVI的固有正电荷（pI = 10.21）促进病毒粒子与靶细胞的附着和融合。一种赖氨酸和精氨酸被丙氨酸取代的SEVI突变形式保留了形成淀粉样纤维的能力，但在结合病毒粒子和增强感染方面存在缺陷。此外，在各种聚阴离子化合物存在的情况下，野生型SEVI与病毒粒子的相互作用以及这些纤维增加感染的能力被消除。这些阴离子聚合物也降低了精液介导的HIV感染增强作用。这些发现表明，SEVI通过作为一种聚阳离子桥来增强病毒感染，该桥中和了HIV病毒粒子与靶细胞之间存在的负电荷排斥。中和SEVI作用并产生HIV杀病毒作用的药物组合是未来杀微生物剂开发的一个有吸引力的方向。
