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Clinical Implications of HIV-1 Rev-Rev Response Element Functional Activity Variation

HIV-1 Rev-Rev 反应元件功能活动变异的临床意义

基本信息

批准号：
10326826
负责人：
Patrick Evan Hager Jackson
金额：
$ 19.18万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-18 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326826
关键词：
Active Learning Address Affect Antigens Applications Grants Basic Science Bioinformatics Biological Assay Cell Nucleus Cells Clinical Communicable Diseases Complex Cytoplasm Cytotoxic T-Lymphocytes Development Development Plans Environment Evaluation Exposure to Failure Future Grant HIV HIV Infections HIV-1 Horizontal Disease Transmission Immune Immune Evasion Immune system Infection International Introns Investigation Investigational Therapies K-Series Research Career Programs Kinetics Lead Lentivirus Lentivirus Vector Life Cycle Stages Maintenance Mediating Mentors Mentorship Messenger RNA Minor Modeling Molecular Biology Molecular Conformation Pathogenesis Patients Peer Review Pharmacology Play Post-Transcriptional Regulation Process Production Prophylactic treatment Proviruses Publications RNA Regulatory Element Research Research Personnel Response Elements Role Route Scientist Selection Criteria Series Structure System Techniques Testing Time TimeLine Training Transcript Translational Research Universities Variant Vertical Disease Transmission Viral Viral Antigens Viral Proteins Virginia Virus Virus Latency Virus Replication Work Writing career career development clinically significant design experience experimental study gag Gene Products high throughput screening improved insight nef Protein novel pathogen pressure prevent programs recruit rev Protein skills success symposium transmission process vaginal mucosa virology

项目摘要

The HIV life cycle requires the export of intron-containing viral mRNAs from the nucleus to the cytoplasm. This process is ordinarily restricted by the cell, but HIV overcomes this check through the interaction of a viral protein, Rev, and an RNA secondary structure, the Rev-Response Element (RRE), found on intron-containing viral transcripts. Variation in the functional activity of the Rev-RRE axis has been observed in viruses taken from patients infected with HIV, but the clinical significance of that variation and its causal mechanism is not clearly understood. Previous studies of a related lentivirus clearly show that Rev-RRE activity variation plays a role in pathogenesis, strongly suggesting that this system is similarly important in HIV infection. It is hypothesized that the Rev-RRE regulatory axis functions as a rheostat which permits viral adaptation to different immune environments. In this K08 Mentored Clinical Scientist Research Career Development Award application, Dr. Patrick Jackson, a fellow in Infectious Diseases at the University of Virginia, proposes to perform a series of studies to illuminate the role of the Rev-RRE system in HIV transmission and in viral latency. First, using a novel high-throughput lentiviral vector assay of Rev-RRE functional activity, the role of this axis in HIV transmission will be examined by comparing Rev-RRE activity in transmitted and circulating viral quasispecies. Second, the Rev-RRE activity of latent proviruses and circulating viruses will be compared. High and low activity Rev-RRE pairs will be tested to see if they cause differences in viral replication kinetics and the production of viral proteins. This phenomenon could underlie the failure of “kick and kill” strategies to cure HIV. Finally, domain swapping experiments will be performed to identify the sequence determinants of both Rev and RRE functional activity. Naturally occurring and chimeric Rev and RRE sequences will be utilized to identify key residues and structures. This research has direct implications for the development of improved pharmacologic prophylaxis for HIV transmission and for improvements in “kick and kill” HIV cures. This research will be conducted at the University of Virginia under the mentorship of Drs. David Rekosh and Marie- Louise Hammarskjold who have a strong track record of training success. Dr. Jackson proposes a career development plan consisting of experiential learning; formal course work in molecular biology, bioinformatics, and grant writing; and structured research and professional mentorship. He proposes a specific timeline for presentation of results at international conferences and in peer reviewed publications, as well as a timeline for future grant applications. This program is designed to situate him as an independent researcher with expertise in HIV virology and a skill set which encompasses a broad set of scientific techniques.

HIV的生命周期需要将含有内含子的病毒mrna从细胞核输出到细胞质。这