ADS-J1 inhibits semen-derived amyloid fibril formation and blocks fibril-mediated enhancement of HIV-1 infection
ADS-J1 inhibits semen-derived amyloid fibril formation and blocks fibril-mediated enhancement of HIV-1 infection
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ADS-J1 抑制精液衍生的淀粉样原纤维形成并阻止原纤维介导的 HIV-1 感染增强
DOI：
10.1128/aac.00385-15
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发表时间：
2015
影响因子：
4.9
通讯作者：
Liu Shuwen
中科院分区：
文献类型：
--
作者：
Xun Tianrong;Li Wenjuan;Chen Jinquan;Yu Fei;Xu Wei;Wang Qian;Yu Ruizhe;Li Xiaojuan;Zhou Xuefeng;Lu Lu;Jiang Shibo;Li Lin;Tan Suiyi;Liu Shuwen
精液源性病毒感染增强因子（SEVI）是由淀粉样纤维组成的，能显著增强HIV-1的感染性。由于其阳离子特性，SEVI通过促进HIV-1与靶细胞的附着和内化来促进病毒性传播。因此，精液来源的淀粉样纤维是杀微生物剂设计的潜在目标。ADS-J1是一种阴离子HIV-1进入抑制剂。在这项研究中，我们探索了ADS-J1的额外功能：抑制SEVI原纤维形成和阻断SEVI介导的病毒感染增强。我们发现ADS-J1与淀粉样蛋白生成肽片段（PAP 248 -286，包含前列腺酸性磷酸酶的氨基酸248至286）结合，从而抑制肽组装成淀粉样蛋白原纤维。此外，ADS-J1与成熟淀粉样纤维结合，并拮抗纤维介导的病毒感染增强。与硫酸纤维素（一种在临床试验中未能阻止HIV-1性传播的聚阴离子）不同，ADS-J1没有显示出促进原纤维形成的能力。更重要的是，ADS-J1与几种抗逆转录病毒药物的组合对精液中的HIV-1感染表现出协同作用，对阴道上皮细胞的细胞毒性很小。我们的研究结果表明，ADS-J1或其衍生物可以被纳入一个组合杀微生物剂，用于预防HIV-1的性传播。
ABSTRACT Semen-derived enhancer of viral infection (SEVI) is composed of amyloid fibrils that can greatly enhance HIV-1 infectivity. By its cationic property, SEVI promotes viral sexual transmission by facilitating the attachment and internalization of HIV-1 to target cells. Therefore, semen-derived amyloid fibrils are potential targets for microbicide design. ADS-J1 is an anionic HIV-1 entry inhibitor. In this study, we explored an additional function of ADS-J1: inhibition of SEVI fibril formation and blockage of SEVI-mediated enhancement of viral infection. We found that ADS-J1 bound to an amyloidogenic peptide fragment (PAP248–286, comprising amino acids 248 to 286 of the enzyme prostatic acid phosphatase), thereby inhibiting peptide assembly into amyloid fibrils. In addition, ADS-J1 binds to mature amyloid fibrils and antagonizes fibril-mediated enhancement of viral infection. Unlike cellulose sulfate, a polyanion that failed in clinical trial to prevent HIV-1 sexual transmission, ADS-J1 shows no ability to facilitate fibril formation. More importantly, the combination of ADS-J1 with several antiretroviral drugs exhibited synergistic effects against HIV-1 infection in semen, with little cytotoxicity to vaginal epithelial cells. Our results suggest that ADS-J1 or a derivative may be incorporated into a combination microbicide for prevention of the sexual transmission of HIV-1.