HARC: HIV accessory and regulatory complexes

点击翻译按钮获取中文摘要

THE HARC CENTER: HIV ACCESSORY AND REGULATORY COMPLEXES OVERALL SUMMARY The HARC Center is an interdisciplinary program that aims to improve our understanding of the interactions between HIV accessory and regulatory proteins and host cellular systems, with the ultimate goal to expand on therapeutic targets and treatment modalities for HIV/AIDS. The HARC Center will focus its efforts on the determination of structures of the accessory and regulatory proteins of HIV-1, with a focus on Tat, Vif and Rev, in complex with their cellular partners, which have not been targets of HIV therapeutic modalities until now. A better molecular understanding of the functions and mechanisms of virus-host complexes may reveal new therapeutic strategies for intervention, including strategies of host-directed therapies, which may escape the limitations of current drug regimens where mutations in the targeted HIV enzymes can diminish drug efficacy. The HARC Center will determine the structures of these virus-host complexes using an integrated “Systems-to- Structure” platform that includes (1) Discovery, through novel methods of functional proteomics and genetics being developed in the HARC Center, (2) Validation through breakthrough CRISPR methods in primary T cells as well as targeted biochemical and functional assays, and (3) Structure Determination using a synthesis of innovative structural techniques developed in previous iterations of the HARC Center to address the large, flexible, heterogeneous and sometimes membrane-associated systems we study. The proposed Research Projects are centered around three themes that serve the Center’s goal. We will explore how HIV inhibits Host restriction factors (Theme 1), study the factors regulating HIV transcription and latency (Theme 2) and investigate virus-host Evolution (Theme 3) across three projects: Structure and evolution of Vif and APOBEC3 (Project 1), Regulation of HIV transcription and latency (Project 2), and Genetics and evolution (Project 3). The HARC Center projects are supported by 4 technology cores covering proteomic approaches (Core 1 - Proteomics), CRISPR screens and endogenous tagging in primary cells to study virus- host function (Core 2 - Genetics), structural biology using cryo-Electron Microscopy, X-ray screening and antibody technologies to determine the structures of HIV virus-host complexes (Core 3 - Structural Biology), and integrative modeling of virus-host complexes (Core 4 - Computational). The overall goals, progress, and administration as well as outreach activities and communications will be overseen by the Administrative Core (Core 5). The Developmental Core (Core 6) will provide training opportunities to young investigators and HARC Center members and award the Collaborative Opportunity Fund to enhance the Center’s overall research theme.