The Surprising Role of Amyloid Fibrils in HIV Infection.
The Surprising Role of Amyloid Fibrils in HIV Infection.
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DOI：
10.3390/biology1010058
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发表时间：
2012-05-29
期刊：
影响因子：
4.2
通讯作者：
Shorter J
中科院分区：
文献类型：
--
作者：
Castellano LM;Shorter J
尽管有30年前的发现，但人类免疫缺陷病毒（HIV）仍在全球范围内威胁到公共卫生。精液是该逆转录病毒和几种内源性肽在精液中传播的主要载体，包括前列腺酸磷酸酶的片段（PAP248-286和PAP85-120）和Semenogelins（SEM1和SEM2）（SEM1和SEM2），将其组装成促进HIV感染的淀粉样蛋白纤维。例如，PAP248-286原纤维称为SEVI（衍生的病毒感染增强剂），最多可增强HIV感染105倍。原纤维通过促进病毒粒子的附着并融合到靶细胞来增强感染性，而可溶性肽无效。重要的是，在低病毒滴度下，刺激作用是模仿艾滋病毒的粘膜传播的最大的，在这种效应中，相对较少的病毒体横穿粘膜屏障。设计一种方法来快速逆转原纤维形成（而不是简单地抑制它）将提供一种创新且急需的预防策略，以通过性途径减少HIV感染。靶向宿主编码的蛋白质构象体代表了靶向病毒机械的传统微生物方法的背离，并且可以通过直接抗病毒方法协同作用。在这里，我们回顾了这些淀粉样蛋白生成肽的鉴定，其作用机理以及抑制其艾滋病毒增强作用的各种策略。
Despite its discovery over 30 years ago, human immunodeficiency virus (HIV) continues to threaten public health worldwide. Semen is the principal vehicle for the transmission of this retrovirus and several endogenous peptides in semen, including fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2), assemble into amyloid fibrils that promote HIV infection. For example, PAP248-286 fibrils, termed SEVI (Semen derived Enhancer of Viral Infection), potentiate HIV infection by up to 105-fold. Fibrils enhance infectivity by facilitating virion attachment and fusion to target cells, whereas soluble peptides have no effect. Importantly, the stimulatory effect is greatest at low viral titers, which mimics mucosal transmission of HIV, where relatively few virions traverse the mucosal barrier. Devising a method to rapidly reverse fibril formation (rather than simply inhibit it) would provide an innovative and urgently needed preventative strategy for reducing HIV infection via the sexual route. Targeting a host-encoded protein conformer represents a departure from traditional microbicidal approaches that target the viral machinery, and could synergize with direct antiviral approaches. Here, we review the identification of these amyloidogenic peptides, their mechanism of action, and various strategies for inhibiting their HIV-enhancing effects.