2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/649160摘要：第一型人類免疫缺陷病毒 (HIV-1) 會感染多種細胞，主要包含了 CD4+ T 淋巴細胞 (lymphocyte) 及巨噬細胞 (macrophage)。HIV-1 通常能穩定存在於被感染的巨噬細胞中，進而感染鄰近的 CD4 +T 淋巴細胞，使 T 細胞急速凋亡 (apoptosis) 而產生人體嚴重的急性病毒血症。HIV-1 感染 CD4+ T 細胞與巨噬細胞時，所造成不同程度上的病毒複製、細胞死亡速率，這些現象仍是現今科學研究中相當熱門的課題。我們發現熱休克蛋白 (Heat shock proteins, HSP) 在不同的血球細胞中有著不同的表現量，我們想要研究HSP 是否在調控 HIV-1 對細胞的易感性 (cell susceptibility) 上扮演了重要的角色。其中HSP70、HSP40、HSP27 與 HSF1 (Heat shock factor 1)，已被證實會增加或抑制 HIV-1 的複製。而我們初步研究有新重要的發現：1). HSP27 在巨噬細胞呈現高表現量；卻在 CD4+ T 淋巴細胞中表現量低。2). HSF1 於 CD4+ T 淋巴細胞大量存在，卻少量存在於單核白血球 (monocyte)、巨噬細胞以及 CD4-淋巴細胞。 我們假設 HSP27 在巨噬細胞中可能扮演了保護角色來抵抗 HIV-1 的感染以及病毒蛋白所造成的細胞凋亡；另一方面，HSF1 在 CD4+ T 淋巴細胞卻有可能會增加 HIV-1的感染並加強病毒的複製。在此計畫，我們將去證實在 HIV-1 感染中，不同的熱休克蛋白是否會影響細胞對於 HIV-1 的易感性，而造成了不同程度上的細胞死亡。藉此找出熱休克蛋白與病毒感染之間的關聯，並期望可以利用熱休克蛋白來發展出創新的 HIV-1 治療策略。<br> Abstract: Both CD4+ T cells and macrophage are targets for HIV-1 infection. HIV-1 infection in macrophage is usually persistent, while infection of CD4 T cells leads to explosive viremia and subsequent rapid T cell apoptosis. The different outcomes upon same virus infection between CD4+ T cells and macrophage have been an important topic to scientists. We want to investigate whether heat shock proteins have different biological roles that regulate cell susceptibility to HIV-1 and cell death, as well as existing variable expression profile among different blood cells. We will focus on heat shock protein 70 (Hsp70), Hsp40, Hsp27, and heat shock factor 1 (HSF1). All the above proteins have been reported to be associated with HIV-1 replication either positively or negatively. Based on western blot analysis, we have verified some new findings: 1). Hsp27 existed in high level in macrophage but very low level in CD4+ T lymphocyte; 2). Large amounts of HSF1 were present in CD4+ T cell but the amounts in monocyte, macrophage, and CD4- lymphocyte were low. We hypothesize that Hsp27 plays a protective role, special in macrophage, against HIV-1 infection and viral protein induced apoptosis; on the other hand, the HSF1 play a positive role to enhance HIV-1 infection and replication, special in activated CD4+ T lymphocyte. In this 3-year project, we want to address whether different HSPs (such as HSP27, HSF1) determine cell susceptibility to HIV-1 infection and modulate cell fate upon HIV-1 infection. We will set up HSP27 and HSF1 knock-down or over-expressed stable clones both in CD4+ T cells and macrophage cell line and examine apoptosis ratio and how HIV-1 replicates in these different cells. Detailed molecular mechanism about how HSP27 and HSF1moderate HIV-1 infection and apoptosis will be further dissected in this project. We believe this project will not only shed the light on HSP and virus infection but also understand how cells behave following virus infection based on the inherent hsp patterns. We expect to develop new strategy for HIV-1 therapy based on HSPs manipulation.