Structural Studies of Human Papillomavirus

项目摘要/摘要 人乳头瘤病毒(HPV)是一种致癌病毒。每年有超过25万人死于 这些癌症，特别是宫颈癌、肛门癌和头颈部(H&N)癌。免疫蛋白被称为 抗体可以预防这些病毒，而成功的疫苗必须诱导这种抗体。当前 疫苗只能保护我们免受宫颈癌和H&N癌15种HPV类型中的两种。更好的和 要更持久地控制HPV感染，需要更好地了解这些抗体是如何保护 是提供这种保护的“最好的”抗体。 我们的研究集中在了解HPV衣壳与人类细胞之间的确切相互作用 一种感染。我们将使用冷冻电子显微镜(Cryo-EM)和计算机驱动的高分辨率技术来 在原子分辨率下定义这些相互作用，首先对衣壳进行更好、更详细的检查。为 几十年来，研究人员一直依赖于各种病毒样颗粒(VLP)的使用，这些病毒样颗粒现在已知具有 不同的特征，特别是在不利于宿主免疫反应的区域。这一特征的一部分 是绘制具有重要功能的次要结构蛋白(L2)的位置和掺入图 进入，并在物种之间保存。了解L2功能将揭示一个重要的目标 直到现在仍然没有特征，可能允许研究人员改变免疫抗体反应的方向 走向一种更有效和更持久的保护性HPV疫苗。最后，我们致力于理解 驱动HPV进入的机制。我们已经开始了解病毒在进入过程中如何改变形状 进入人类细胞。靶向构象变化的病毒是创造新的 用来阻止感染的药物。

Project Summary/Abstract Human papillomaviruses (HPVs) are cancer-causing viruses. More than 250,000 people die each year from these cancers, particularly cervical, anal, and head and neck (H&N) cancers. Immune proteins known as antibodies can protect against these viruses and successful vaccines must induce such antibodies. Current vaccines can protect us against only two of the 15 HPV types found in cervical and H&N cancers. Better and more lasting control of HPV infections requires improved knowledge of how these antibodies protect and which are the “best” antibodies to provide this protection. Our studies are focused at understanding the exact interactions between HPV capsids and human cells during an infection. We will use cryo-electron microscopy (cryo-EM) and computer-driven high resolution techniques to define these interactions at atomic resolution, starting with a better more detailed examination of the capsids. For decades researchers have relied on the use of various virus like particles (VLPs) that are now known to have different characteristics, especially in the regions that illicit a host immune response. Part of this characterization is to map the location and incorporation of the minor structural protein (L2) that has important function during entry and is conserved across species. Understanding L2 function will reveal a significant target that has remained uncharacterized until now and may allow researchers to redirect the immune antibody response towards a more effective and long-lasting protective HPV vaccine. Finally, we are engaged in understanding the mechanisms that drive entry of HPV. We have begun to understand how the virus changes shape during entry into human cells. Targeting the conformational changing virus is an important new direction for creating new drugs to stop infection.