Virus-Host Interactions that Modulate Early Steps of Human Papillomavirus Infecti

调节人乳头瘤病毒感染早期步骤的病毒-宿主相互作用

• 批准号: 8187395
• 负责人: Dohun Pyeon
• 金额: $ 30.21万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8187395
• 关键词: Anus; Autophagocytosis; Autophagosome; Cancer Etiology; Cell Cycle Progression; Cell Nucleus; Cells; Cervical; Cessation of life; Cytoplasm; DNA; DNA Viruses; Developing Countries; Development; Future; Gene Expression; Genome; Genotype; Goals; HPV-High Risk; Head and neck structure; Host Defense Mechanism; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Imaging technology; Immune response; In Vitro; Incidence; Infection; Integration Host Factors; International Agency for Research on Cancer; Label; Laboratories; Length; Lesion; Life; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Methods; Microtubules; Mitosis; Modeling; Movement; Natural Immunity; Nuclear; Nuclear Envelope; Papillomavirus Infections; Pathway interactions; Pattern recognition receptor; Plasmids; Play; Premalignant; Production; Receptor Signaling; Religion and Spirituality; Research; Role; Squamous cell carcinoma; System; Technology; Testing; Time; Toll-Like Receptor 2; United States; Vaccination; Vaccines; Vagina; Viral; Viral Genes; Viral Genome; Virion; Virus; Virus Diseases; base; cell type; cost; in vivo; innovation; keratinocyte; mouse model; novel; particle; pathogen; prevent; prophylactic; response; social; trafficking; tumor progression; viral DNA; virus host interaction

DESCRIPTION (provided by applicant): The long-term goals of our research are to understand the mechanisms of HPV-host interactions necessary for establishing and maintaining HPV infections in human keratinocytes throughout HPV-associated cancer progression. Human papillomaviruses (HPVs) are the most common sexually transmitted pathogen, causally associated with a growing number of human cancers including cervical, vaginal, penile, anal, head/neck, and other squamous carcinomas, causing almost half a million deaths worldwide each year (International Agency for Research on Cancer). To establish persistent infections, the virus must enter the nucleus and establish its genome as a nuclear plasmid. However, little is known about how HPV genome enters the nucleus and establishes its replication, due to technical limitations. To achieve our goals, we will: 1) define the role of host cell mitosis and microtubule reorganization for HPV DNA nuclear entry in human keratinocytes; and 2) investigate host innate responses and its roles for early steps of HPV infection in primary keratinocytes in vitro and in vivo. In these studies, we will develop reliable HPV DNA labeling systems with various fluorescent tags and track the movement of HPV DNA in live human keratinocytes, using infectious HPV virions and real time imaging technology. In addition, we will test alterations of HPV infectivity, DNA entry into the nucleus, and genome replication by knockdown of host factors involved in mitosis, microtubule network, and host innate immunity. Recently developed prophylactic HPV vaccines should eventually reduce infections by some HPV genotypes. However, because the vaccines do not cover all HPVs and do not eliminate existing infections, there remains an urgent need to develop new means of intervening in HPV infections and preventing cancer progression. Our studies will provide further understanding of mechanisms employed by HPVs to establish infections and thereby identify pathways to target for preventing HPV-associated cancers. PUBLIC HEALTH RELEVANCE: Human papillomaviruses (HPVs) are the most common sexually transmitted pathogen, causally associated with many human cancers. Although the virus must enter the nucleus and establish its genome as a nuclear plasmid for persistent infection and cancer development, little is known about how HPV genome enters the nucleus and establishes its replication. The goals of our research are to understand the mechanisms of HPV-host interactions necessary for establishing and maintaining HPV infections in primary keratinocytes in vitro and in vivo.

描述（由申请人提供）：我们研究的长期目标是了解HPV-宿主相互作用的机制，这些机制是在HPV相关癌症进展过程中在人角质形成细胞中建立和维持HPV感染所必需的。人乳头瘤病毒（HPV）是最常见的性传播病原体，与越来越多的人类癌症（包括宫颈癌、阴道癌、阴茎癌、肛门癌、头颈癌和其他鳞状细胞癌）有因果关系，每年在全世界造成近50万人死亡（国际癌症研究机构）。为了建立持续感染，病毒必须进入细胞核并将其基因组建立为核质粒。然而，由于技术限制，人们对HPV基因组如何进入细胞核并建立其复制知之甚少。为了实现我们的目标，我们将：1）确定宿主细胞有丝分裂和微管重组对人角质形成细胞中HPV DNA核进入的作用; 2）研究宿主先天性反应及其在体外和体内原代角质形成细胞中HPV感染早期步骤中的作用。在这些研究中，我们将开发可靠的HPV DNA标记系统与各种荧光标签和跟踪HPV DNA在活的人角质形成细胞中的运动，使用感染性HPV病毒粒子和真实的时间成像技术。此外，我们将测试HPV感染性的改变，DNA进入细胞核，并通过敲除参与有丝分裂，微管网络和宿主先天免疫的宿主因子进行基因组复制。最近开发的预防性HPV疫苗最终应减少某些HPV基因型的感染。然而，由于疫苗不能覆盖所有HPV，也不能消除现有的感染，因此仍然迫切需要开发干预HPV感染和预防癌症进展的新方法。我们的研究将进一步了解HPV建立感染的机制，从而确定预防HPV相关癌症的靶向途径。 公共卫生相关性：人乳头瘤病毒（HPV）是最常见的性传播病原体，与许多人类癌症有因果关系。尽管病毒必须进入细胞核并将其基因组建立为持续感染和癌症发展的核质粒，但人们对HPV基因组如何进入细胞核并建立其复制知之甚少。我们的研究目的是了解HPV-宿主相互作用的机制，建立和维持HPV感染的原代角质形成细胞在体外和体内。