Nef通过与CD14相互作用激活TLR4信号通路从而调控HIV-1复制的分子机制研究

艾滋病（AIDS）严重威胁人类健康，HIV-1 Nef蛋白在艾滋病发病过程中起着至关重要的作用，包括增强HIV-1在感染细胞中的复制和存活以及促进HIV-1在体内的传播，故进一步研究Nef蛋白的功能非常有必要。我们利用酵母双杂交筛选系统，以Nef做诱饵蛋白，筛选到膜蛋白CD14，后续的验证实验进一步证实了Nef和CD14的相互作用。CD14是Toll样受体4（TLR4）和MD2的共同受体，它为人所熟知的功能是识别细菌的脂多糖（LPS），此外还能识别多种病毒的蛋白。本项目中，我们将在分子和细胞水平研究Nef与CD14相互作用对于TLR4信号通路的激活作用，以及由此产生的对不同嗜性表型HIV-1病毒株复制和侵染性的调控。通过此研究，可解释在HIV-1感染的疾病进展过程中为什么通常会出现M嗜性HIV-1病毒株向T嗜性或双重嗜性HIV-1病毒株转变这一病程现象。

Human Acquired immunodeficiency syndrome (AIDS) is a serious threat to health. HIV-1 Nef protein plays a critical role in AIDS pathogenesis by enhancing viral replication and survival within infected cells and by facilitating its spread in vivo, so a further study on the functions of Nef is necessary. By yeast two hybrid screening system, a membrane protein called CD14 was captured using Nef as bait protein. The interaction between Nef and CD14 was verified by additional confirmatory experiments. CD14, which acts as a co-receptor along with Toll-like receptor 4 (TLR4) and MD-2, is well-known for recognizing bacterial lipopolysaccharide (LPS), and is also involved in recognition of several viral proteins. In this study, the molecular mechanism of activation of TLR4 signaling pathway by Nef binding to CD14 will be well explored in cells, and the regulation of replication and infectivity of different tropic phenotypes of HIV-1 strains by the TLR4 signaling pathway will also be characterized. These investigations shall explain the phenotypic switch from M- to T-tropic or dual-tropic HIV-1 strains that has been frequently observed during HIV-1 disease progression.