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