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Regulation of HIV-1 and related lentiviruses by the DNA damage response

DNA 损伤反应对 HIV-1 和相关慢病毒的调节

基本信息

批准号：
9204186
负责人：
Oliver I Fregoso
金额：
$ 16万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-02 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9204186
关键词：
AIDS/HIV problem Address Affect Antiviral Agents Biochemistry Biology CRISPR/Cas technology Cell Cycle Arrest Cells Characteristics Complex Conflict (Psychology)DNA DNA Damage DNA Repair Data Deoxyribonuclease I Developing Countries Environment Evolution Family Foundations Funding Gene Expression Genes Goals HIV HIV-1 Health Homeostasis Human Human Biology Immune response Infection Integration Host Factors Knowledge Light Molecular Molecular Biology Molecular Virology Nature Pathogenesis Pathway interactions Primate Lentiviruses Primates Proteins RNA Recording of previous events Recruitment Activity Regulation Research Research Project Grants Role Signaling Protein Structure Subfamily lentivirinae Testing Underserved Population Variant Viral Viral Proteins Virus Work cofactor fight against follow-up in vivo interdisciplinary approach novel pandemic disease pathogen research study response success ubiquitin ligase viral transmission virus host interaction vpr Gene Products vpr Genes

项目摘要

PROJECT SUMMARY/ABSTRACT HIV presents a major obstacle to human health, particularly in developing nations. The success of HIV is largely due to its ability to adapt to the human host environment and circumvent our innate immune responses. This is principally achieved through viral accessory proteins, which engage cellular proteins to both antagonize host antiviral factors and usurp host cellular machinery. The understanding of these interactions is critical to our fight against HIV. My proposal will determine how cellular proteins involved in the DNA damage response interact with HIV and related lentiviruses to modulate their lifecycle. I hypothesize that the DNA damage response is both anti-viral and pro-viral, as this protein-signaling cascade can sense aberrant DNA and RNA structures and can directly affect cellular homeostasis. HIV belongs to a family of viruses called lentiviruses that infect at least 40 primate species, including humans. Using the natural variation present in lentiviruses, I will determine how Vpr, a viral accessory protein that is common to all extant lentiviruses, has evolved to engage the host DNA damage response through both activation of DNA damage response pathways and direct interactions with DNA damage response proteins. I will specifically test the hypothesis that Vpr directly causes DNA damage in order to activate this cellular response. Furthermore, I will determine if engagement with the DNA damage response is a conserved, and therefore important, function for all lentiviruses, or if it is specific to HIV-1, and thus critical for adaptations and pathogenesis in humans. In addition, I will expand our knowledge of the role of the DNA damage response in lentiviral biology by identifying novel regulators of HIV-1 that are also involved in this cellular response. I will perform an evolution- guided screen to identify candidate DNA damage response proteins and pathways, and I will follow up these hits with specific experiments to elucidate their roles. These studies will identify the DNA damage response as important regulators of HIV-1 and related lentiviruses. They will shed light on lentiviral evolution, on the cellular response to infection, and on the multifaceted roles of the DNA damage response, while helping to identify potential antiviral targets in our fight against HIV.

项目总结/文摘