"Finding a viral needle in a nuclear haystack: molecular mechanism of HIV detection by NONO-cGAS in the nucleus (2022-08-LAHAYE_MANEL)" project details

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General information

Application closed

2022-08-LAHAYE_MANEL

HIV; Innate immunity; Virus detection; Nuclear sensors; cGAS-STING pathway

Finding a viral needle in a nuclear haystack: molecular mechanism of HIV detection by NONO-cGAS in the nucleus

Director(s) and team

Xavier Lahaye & Nicolas Mane

Innate Immunity

Abstract

The ability of cells to detect viruses is essential for their defense. The cGAS-STING pathway has emerged in the recent years as the main pathway for sensing viral DNA in the cytosol across the tree of life. In mammals, this detection activates a signaling cascade that culminates into the production of antiviral interferons and immune responses.   However, most DNA viruses and some RNA viruses enter the nucleus to replicate in cells. The viral sensors in the nucleus are largely unknown. The nucleus is so full of DNA and RNA already that finding a virus is like finding a needle in a haystack. Recent studies from our lab (Lahaye et al. Immunity 2013, Gentili et al. Science 2015, Silvin et al. Science Immunology 2017, Lahaye et al. Cell 2018, Gentili et al. Cell Reports 2019) have shown that human dendritic cells and macrophages can detect HIV in the nucleus. We discovered that HIV is detected by a duo of sensors: the NONO proteins first detects the viral capsid protein. Then, the cGAS protein detects the viral DNA. This activates cGAS in the nucleus, leading to activation of the cGAS-STING-interferon signaling pathway.   The PhD will use interdisciplinary approaches in immunology, virology, biochemistry and biophysics to ask the following questions: How do NONO and cGAS manage to detect locally HIV, as it enters the nucleus? What is the biochemical reaction taking place and how is it isolated from the rest of the nucleus? Can this reaction be modeled using a "HIV sensing in a test tube" assay? By addressing these questions, the PhD will provide a crucial understanding of how viral sensors detect viruses in the nucleus.

Requirements to apply for the PhD thesis project

The PhD candidate should be intensely motivated to study molecular mechanisms and to perform experiments in molecular virology, molecular innate immunity, biochemistry and biophysics. A strong background in biochemistry of proteins and DNA is recommended. A previous academic lab experience in molecular biology and biochemistry is highly desirable.