Generating SEVI disaggregases to prevent HIV infection

描述（由申请人提供）：人类免疫缺陷病毒1型（HIV-1）是获得性免疫缺陷综合征（AIDS）的病原体，已感染全球约6000万人，并导致2500多万人死亡。性传播是HIV-1感染的主要途径，最近在精液中发现了促进这种感染途径的因素。前列腺酸性磷酸酶的片段是精液的主要成分，并形成淀粉样纤维，其结合HIV病毒体，并可促进高达105倍的感染。因此，一种潜在的预防策略是部署消除这些淀粉样蛋白形式的药物，这些淀粉样蛋白形式被称为精液衍生的病毒感染增强剂（SEVI）原纤维。不幸的是，淀粉样纤维非常稳定且难以根除。换句 它们与各种致命的神经退行性疾病有关。然而，各种微生物已经利用淀粉样蛋白形式用于有益的目的，并且已经进化出可以快速逆转淀粉样蛋白形成的系统。一种天然蛋白质已经出现，它以前所未有的敏捷性分解淀粉样纤维：蛋白质解聚酶，HSP 104。热休克蛋白104能迅速溶解几种蛋白质的淀粉样蛋白，包括酵母朊病毒蛋白Sup 35和Ure 2，以及？突触核蛋白，它在帕金森病中形成淀粉样纤维。我们假设Hsp 104或SEVI优化的变体可以快速溶解或重塑SEVI原纤维，从而减少SEVI增强的HIV感染。因此，我们的目标是：（1）开发快速分解SEVI原纤维的Hsp 104变体，（2）确定分解产物是否降低了促进HIV感染的能力。这些研究将为开发SEVI解聚剂作为预防剂提供基础，最终目标是将其纳入凝胶或溶液中，溶解精液中的SEVI纤维，减少艾滋病毒的性传播。逆转原纤维形成（而不是简单地抑制它）和阻止艾滋病毒的性传播的能力将为全球艾滋病毒/艾滋病流行提供一个强大和急需的武器。我们靶向宿主蛋白构象体（SEVI原纤维）的方法与靶向病毒的传统杀微生物方法有根本不同，预计这种策略将与直接抗病毒策略协同作用。

DESCRIPTION (provided by applicant): Human immunodeficiency virus type-1 (HIV-1), the causative agent of acquired immune deficiency syndrome (AIDS), has infected ~60 million people worldwide and caused over 25 million deaths. Sexual transmission is the major route of HIV-1 infection and factors that promote this infectious route have recently been identified in semen. Fragments of prostatic acid phosphatase are a major component of semen and form amyloid fibrils that bind HIV virions and can promote infection by several orders of magnitude up to 105-fold. Therefore, a potential preventative strategy is to deploy agents that eliminate these amyloid forms, which are termed Semen-derived Enhancer of Virus Infection (SEVI) fibrils. Unfortunately, amyloid fibrils are notoriously stable and difficult to eradicate. In other settings, they are connected with various fatal neurodegenerative disorders. However, various microbes have harnessed the amyloid form for beneficial purposes, and systems have evolved that can rapidly reverse amyloid formation. One natural protein has emerged that resolves amyloid fibrils with unprecedented alacrity: the protein disaggregase, Hsp104. Hsp104 rapidly solubilizes amyloid forms of several proteins, including yeast prion proteins Sup35 and Ure2, as well as ?-synuclein, which forms amyloid fibrils in Parkinson's disease. We hypothesize that Hsp104 or SEVI-optimized variants can be generated to rapidly dissolve or remodel SEVI fibrils and thereby diminish SEVI-enhanced HIV infection. Thus, we aim to: (1) Develop Hsp104 variants that rapidly disassemble SEVI fibrils~ and (2) Determine whether disassembled products have diminished ability to promote HIV infection. These studies will provide the foundations for developing SEVI disaggregases as preventative agents with the ultimate goal of incorporating them into a gel or solution that dissolves SEVI fibrils in semen and reduces sexual transmission of HIV. The ability to reverse fibril formation (rather than simply inhibit it) and blck sexual transmission of HIV will provide a powerful and much needed weapon against the global HIV/AIDS pandemic. Our approach of targeting a host protein conformer (SEVI fibrils) is fundamentally different from traditional microbicidal approaches that target the virus, and this strategy is anticipated to synergize with direct antiviral strategies.