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近日，来自宾夕法尼亚大学等处的科学家们表示，目前有两种方法可以抵御AIDS，利用热激蛋白或小分子来攻击HIV起始感染阶段精液中的原纤维；HIV经常会通过精液在个体间传播，其作为男性的生殖液包含有大量名为淀粉样纤维的蛋白片段沉积，这些淀粉样纤维可以帮助病毒吸附到人类细胞上来促进HIV的传播，而研究者也推测降低精液中淀粉样纤维的疗法或可有效降低HIV的传播。
刊登在Chemistry & Biology上的一篇研究论文中，研究者James Shorter报道了酵母中的一种名为Hsp104的热激蛋白可以有效攻击精液中的淀粉样纤维，首先Hsp104及一种增强的工程化突变体会直接将原纤维重塑为非淀粉样纤维形式；同时研究者还制造出了失活的Hsp104支架，该支架可以将原纤维重新组装成为大尺寸的良性部件，最终研究者通过修饰Hsp104来使其同酶类作用最终使得精液中的原纤维发生不可逆地降解。
每一种策略都会降低淀粉样纤维促进HIV感染的能力，因此这种新方法或许是一种抑制HIV传播的新型策略；刊登在国际杂志eLife上的另一篇报道中，研究者则描述了第二种方法，即利用一种小分子来干扰精液中淀粉样纤维的结构，进而抑制HIV感染，这种名为CLR01的分子同时也可以攻击HIV病毒自身。
钳形结构的CLR01分子不仅可以干扰原纤维的形成，还会分解已经形成的原纤维结构，CLR01还会通过感染病毒颗粒的外膜结构来抑制HIV颗粒同原纤维的相互作用；在CLR01分子存在的情况下人类细胞受包含HIV精液感染的可能性会降低100倍。研究者Shorter说道，CLR01分子被认为可以作为新型疗法来帮助降低HIV的传播，而且CLR01分子并不会细胞膜的功能，这就说明该分子可以被安全插入到阴道润滑剂中来帮助抵御HIV的感染。
下一步研究者将在非人类的灵长类动物机体中评估两种疗法的安全性和有效性，研究者希望CLR01分子疗法是最有效的抵御HIV传播的疗法，后期研究者们还将进行更多深入的研究来开发更多抑制HIV传播的新疗法。
Laura M. Castellano, Stephen M. Bart, Veronica M. Holmes, Drew Weissman, James Shorter
Naturally occurring proteolytic fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2) form amyloid fibrils in seminal fluid, which capture HIV virions and promote infection. For example, PAP248-286 fibrils, termed SEVI (semen-derived enhancer of viral infection), can potentiate HIV infection by several orders of magnitude. Here, we design three disruptive technologies to rapidly antagonize seminal amyloid by repurposing Hsp104, an amyloid-remodeling nanomachine from yeast. First, Hsp104 and an enhanced engineered variant, Hsp104A503V, directly remodel SEVI and PAP85-120 fibrils into non-amyloid forms. Second, we elucidate catalytically inactive Hsp104 scaffolds that do not remodel amyloid structure, but cluster SEVI, PAP85-120, and SEM1(45–107) fibrils into larger assemblies. Third, we modify Hsp104 to interact with the chambered protease ClpP, which enables coupled remodeling and degradation to irreversibly clear SEVI and PAP85-120 fibrils. Each strategy diminished the ability of seminal amyloid to promote HIV infection, and could have therapeutic utility. Lump E1, Castellano LM2, Meier C3, Seeliger J4, Erwin N4, Sperlich B4, Stürzel CM1, Usmani S1, Hammond RM2, von Einem J5, Gerold G6, Kreppel F7, Bravo-Rodriguez K8, Pietschmann T6, Holmes VM9, Palesch D1, Zirafi O1, Weissman D9, Sowislok A10, Wettig B10, Heid C10, Kirchhoff F1, Weil T3, Klärner FG11, Schrader T10, Bitan G12, Sanchez-Garcia E8, Winter R4, Shorter J2, Münch J1.
Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.
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发表于 2016-3-14 09:58:47
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