Structural Studies of Human Papillomavirus

人乳头瘤病毒的结构研究

• 批准号: 10913875
• 负责人: Susan Hafenstein
• 金额: $ 64.29万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-13 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10913875
• 关键词: Address; Affect; Affinity; Antibodies; Antibody Response; Antibody-mediated protection; Basal Cell; Binding; Capsid; Capsid Proteins; Cells; Cervical; Characteristics; Collaborations; Communities; Computers; Cryoelectron Microscopy; Epitopes; Genome; Head Cancer; Head and Neck Cancer; Healthcare; Human; Human Papilloma Virus Vaccine; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immune; Immune response; Immunologics; Infection; Knowledge; L2 viral capsid protein; Life Cycle Stages; Link; Location; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Maps; Minor; Molecular; Molecular Biology; Molecular Conformation; Monoclonal Antibodies; Neck Cancer; Patients; Persons; Pharmaceutical Preparations; Process; Production; Proteins; Public Health; Research; Research Personnel; Resolution; Scheme; Shapes; Structural Protein; Structure; System; Techniques; Throat Cancer; Time; Vaccine Design; Vaccines; Virus; Virus-like particle; aged; design; effective therapy; improved; men; non-smoking; novel therapeutics; particle; pathogenic virus; receptor; response; stoichiometry; three dimensional structure; vaccine development

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.

项目摘要/摘要 人乳头瘤病毒（HPV）是引起癌症的病毒。每年有25万人死亡 这些癌症，尤其是宫颈，肛门和头颈（H＆N）癌症。免疫蛋白被称为 抗体可以预防这些病毒，成功的疫苗必须诱导此类抗体。当前的 疫苗只能保护我们免受宫颈和H＆N癌症中15种HPV类型中的两种。更好 对HPV感染的更多持久控制需要提高对这些抗体的保护以及哪些抗体的了解 是提供此保护的“最佳”抗体。 我们的研究集中于了解HPV衣壳与人类细胞之间的确切相互作用 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 从原子分辨率下定义这些相互作用，首先要对衣壳进行更好的详细检查。为了 数十年的研究人员已经营救了使用各种病毒（例如颗粒（VLP））的使用，这些病毒现在已知 不同的角色，尤其是在非宿主免疫响应的地区。该特征的一部分 是绘制次要结构蛋白（L2）的位置和公司，该蛋白（L2）在 进入并跨物种配置。了解L2功能将揭示一个重要的目标 直到现在仍然没有表征，并且可能允许研究人员重定向免疫抗体反应 采取更有效，更持久的保护HPV疫苗。最后，我们参与了解 驱动HPV进入的机制。我们已经开始了解该病毒在进入过程中的形状如何变化 进入人类细胞。针对构象变化病毒是创建新的新方向的重要新方向 停止感染的药物。

项目成果

High resolution cryo EM analysis of HPV16 identifies minor structural protein L2 and describes capsid flexibility.

• DOI: 10.1038/s41598-021-83076-5
• 发表时间: 2021-02-10
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Goetschius DJ;Hartmann SR;Subramanian S;Bator CM;Christensen ND;Hafenstein SL
• 通讯作者: Hafenstein SL

Cryo EM Analysis Reveals Inherent Flexibility of Authentic Murine Papillomavirus Capsids.

• DOI: 10.3390/v13102023
• 发表时间: 2021-10-07
• 期刊: Viruses
• 作者: Hartmann SR;Goetschius DJ;Hu J;Graff JJ;Bator CM;Christensen ND;Hafenstein SL
• 通讯作者: Hafenstein SL