Polyanionic candidate microbicides accelerate the formation of semen-derived amyloid fibrils to enhance HIV-1 infection.
Polyanionic candidate microbicides accelerate the formation of semen-derived amyloid fibrils to enhance HIV-1 infection.
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聚阴离子候选杀菌剂加速精液衍生淀粉样原纤维的形成以增强 HIV-1 感染
DOI：
10.1371/journal.pone.0059777
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
Tan S;Lu L;Li L;Liu J;Oksov Y;Lu H;Jiang S;Liu S
聚阴离子候选杀微生物剂，包括硫酸纤维素、角叉菜胶、PRO 2000，在预防HIV-1传播方面被证明是无效的，甚至硫酸纤维素在III期疗效试验中也显示出HIV感染的风险增加。精液在HIV-1性传播中起着关键作用。具体而言，由精液中前列腺酸性磷酸酶（PAP）片段形成的淀粉样纤维（SEVI）可显著增强HIV-1感染。在这里，我们研究了聚阴离子和PAP 248 -286（SEVI的原型肽）之间的相互作用，以了解聚阴离子候选杀微生物剂在临床试验中失败的可能原因。我们发现阴离子聚合物可以有效地促进SEVI原纤维的形成，最有可能是由聚阴离子和PAP 248 -286之间的自然静电相互作用介导的，如酸性非变性PAGE和Western印迹所揭示的。在存在或不存在PAP 248 -286或精液的情况下，评价了聚阴离子的总体抗HIV-1活性。在病毒感染试验中，聚阴离子/PAP 248 -286或含有游离的、未结合的聚阴离子分子的聚阴离子/精液混合物的上清液显示抗病毒效力普遍降低，而含有由聚阴离子结合的PAP 248 -286形成的淀粉样蛋白原纤维的颗粒显示病毒感染的加重增强。总的来说，从药物-宿主蛋白质相互作用的角度来看，我们的研究表明，聚阴离子促进SEVI纤维形成，促进HIV-1感染，从而突出了聚阴离子在临床试验中失败的分子机制和药物-精液相互作用在评估候选杀微生物剂抗HIV-1疗效中的重要性。
Polyanionic candidate microbicides, including cellulose sulfate, carrageenan, PRO 2000, were proven ineffective in preventing HIV-1 transmission and even cellulose sulfate showed increased risk of HIV acquisition in the Phase III efficacy trials. Semen plays critical roles in HIV-1 sexual transmission. Specifically, amyloid fibrils formed by fragments of prostatic acidic phosphatase (PAP) in semen termed semen-derived enhancer of virus infection (SEVI) could drastically enhance HIV-1 infection. Here we investigated the interaction between polyanions and PAP248-286, a prototype peptide of SEVI, to understand the possible cause of polyanionic candidate microbicides to fail in clinical trials. We found anionic polymers could efficiently promote SEVI fibril formation, most likely mediated by the natural electrostatic interaction between polyanions and PAP248-286, as revealed by acid native PAGE and Western blot. The overall anti-HIV-1 activity of polyanions in the presence or absence of PAP248-286 or semen was evaluated. In the viral infection assay, the supernatants of polyanions/PAP248-286 or polyanions/semen mixtures containing the free, unbound polyanionic molecules showed a general reduction in antiviral efficacy, while the pellets containing amyloid fibrils formed by the polyanion-bound PAP248-286 showed aggravated enhancement of viral infection. Collectively, from the point of drug-host protein interaction, our study revealed that polyanions facilitate SEVI fibril formation to promote HIV-1 infection, thus highlighting a molecular mechanism underlying the failure of polyanions in clinical trials and the importance of drug-semen interaction in evaluating the anti-HIV-1 efficacy of candidate microbicides.
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影响因子：
3.7
作者：
Martellini JA;Cole AL;Svoboda P;Stuchlik O;Chen LM;Chai KX;Gangrade BK;Sørensen OE;Pohl J;Cole AM
通讯作者：
Cole AM
影响因子：
3.3
作者：
Kim KA;Yolamanova M;Zirafi O;Roan NR;Staendker L;Forssmann WG;Burgener A;Dejucq-Rainsford N;Hahn BH;Shaw GM;Greene WC;Kirchhoff F;Münch J
通讯作者：
Münch J
影响因子：
56.3
作者：
Cutler, Blayne;Justman, Jessica
通讯作者：
Justman, Jessica
影响因子：
4.8
作者：
Martellini, Julie A.;Cole, Amy L.;Cole, Alexander M.
通讯作者：
Cole, Alexander M.
影响因子：
2.9
作者：
Bourgault S;Solomon JP;Reixach N;Kelly JW
通讯作者：
Kelly JW