HIV transcellular and transsynaptic penetration of mucosal epithelium

HIV跨细胞和跨突触渗透粘膜上皮

• 批准号: 8104243
• 负责人: SHAROF M TUGIZOV
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-02 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104243
• 关键词: AIDS prevention; Adult; Agrin; Anatomic Sites; CCR5 gene; CXCR4 gene; Cell Adhesion; Cell Adhesion Molecules; Cells; Cellular Membrane; Cervix Uteri; Clinical; Data; Development; Drug Design; Endocytosis; Environment; Epithelial; Epithelial Cells; Epithelium; Galactosylceramides; Genital system; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; Heparan Sulfate Proteoglycan; Highly Active Antiretroviral Therapy; Human; Human body; Immune; Individual; Infant; Infection; Integrins; Knowledge; Lead; Local Microbicides; Mediating; Membrane; Methods; Molecular; Neonatal; Oral mucous membrane structure; Oropharyngeal; Pathway interactions; Penetration; Play; Preventive; Process; Proteins; Risk; Role; Site; Stratification; Surface; Synapses; Systemic infection; Therapeutic; Tissues; Vaccines; Vertical Disease Transmission; Viral; Virion; Virus; Work; antileukoprotease; antiretroviral therapy; basolateral membrane; beta-defensin-2; fetal; gastrointestinal; gastrointestinal epithelium; human SLPI protein; intestinal epithelium; intraepithelial; novel strategies; oral HIV; oral cavity epithelium; prevent; protein expression; public health relevance; receptor; success; synaptogenesis; transcytosis; transmission process

DESCRIPTION (provided by applicant): Mucosal epithelia are the first tissue sites of contact of HIV with the human body during the course of infection, and these play a critical role in determining its success in establishing systemic infection. We have also shown that the efficiency of transcytotic penetration by HIV varies with the degree of stratification of the mucosal epithelium, as well as with the levels of expression of the anti-HIV innate proteins beta-defensin 2 and 3, and secretory leukocyte protease inhibitor (SLPI). We have shown that HIV transmission through mucosal epithelial cells can occur by transcytotic and between epithelial cells by transsynaptic penetration. Spread from epithelial cells to immune cells by transsynaptic transmission may then lead to systemic HIV infection. Transmission through adult mucosal epithelium such as that of the cervix, and across fetal/neonatal oral or intestinal epithelium remain important clinical problems. There are currently no vaccines available to reduce HIV transmission and other preventive approaches such as administering antiretroviral therapy to exposed individuals may not work since neither transcytosis nor transsynaptic transmission require viral replication or fusion of viral membranes with cellular membranes. New methods to reduce HIV transmission across mucosal epithelia are urgently needed, but to develop these methods, a better understanding of the molecular mechanisms of HIV transcytotic and transsynaptic transmission across epithelial surfaces is critical. Accordingly, the specific aims of this proposal are: (1) To determine the mechanisms of transcytotic and transsynaptic spread of HIV through mucosal epithelia; (2) To determine the role of epithelial anti-HIV innate proteins in HIV transmission across mucosal epithelia. The data obtained from this proposal will greatly advance current knowledge about the mechanisms of HV transmission across mucosal epithelia and will open new avenues for designing drugs that may specifically block HIV passage across these epithelia. PUBLIC HEALTH RELEVANCE: HIV transmission via mucosal epithelium is one of the key initial steps in establishing HIV infection but this process remains poorly understood. This study will characterize the different ways used by HIV to pass through epithelium to infect immune cells, and the various defenses used by epithelial cells to inactivate HIV. Knowledge obtained from these studies may lead to the development of new approaches to prevent HIV infection.

描述（由申请方提供）：粘液上皮是HIV在感染过程中与人体接触的第一个组织部位，这些部位在确定其是否成功建立全身感染方面起着关键作用。我们还表明，HIV的胞吞渗透效率随粘膜上皮的分层程度以及抗HIV先天蛋白β-防御素2和3以及分泌性白细胞蛋白酶抑制剂（SLPI）的表达水平而变化。我们已经证明，HIV通过粘膜上皮细胞的传播可以通过跨细胞吞噬发生，也可以通过跨突触渗透在上皮细胞之间发生。通过跨突触传递从上皮细胞传播到免疫细胞，然后可能导致系统性HIV感染。通过成人粘膜上皮（如子宫颈粘膜上皮）和胎儿/新生儿口腔或肠上皮的传播仍然是重要的临床问题。目前没有疫苗可用于减少艾滋病毒传播，其他预防方法，如对接触艾滋病毒的个体进行抗逆转录病毒治疗可能不起作用，因为转胞吞作用和跨突触传播都不需要病毒复制或病毒膜与细胞膜融合。迫切需要减少HIV跨粘膜上皮传播的新方法，但要开发这些方法，更好地了解HIV跨上皮表面的跨胞吞和跨突触传播的分子机制至关重要。因此，本提案的具体目标是：（1）确定HIV通过粘膜上皮细胞的跨胞吞和跨突触传播的机制;（2）确定上皮抗HIV固有蛋白在HIV跨粘膜上皮细胞传播中的作用。从该提案中获得的数据将大大推进目前关于HV跨粘膜上皮传播机制的知识，并将为设计可能特异性阻断HIV跨这些上皮传播的药物开辟新途径。 公共卫生相关性：HIV通过粘膜上皮传播是HIV感染的关键初始步骤之一，但这一过程仍然知之甚少。这项研究将描述艾滋病毒通过上皮细胞感染免疫细胞的不同方式，以及上皮细胞对艾滋病毒的各种防御。从这些研究中获得的知识可能会导致开发新的方法来预防艾滋病毒感染。