MRC AMED - The HDAC6/USP7 axis in enveloped RNA viral infection

Influenza A virus (IAV) causes annual epidemics and occasional pandemics with continuous threat of emerging and potentially lethal strains derived from reassortment with avian or swine IAV. In addition to development of a universal influenza vaccine, a deeper understanding of cell biology of IAV infections is needed to discover antiviral strategies that target cellular proteins and pathways. Viral uncoating is an early step in infection that is poorly understood, but we think that the host cell factors involved can be targeted effectively as an antiviral strategy. IAV entry and uncoating is well-studied compared to many enveloped RNA viruses. Uncoating requires a ubiquitin-mediated, misfolded protein degradation pathway known as aggresome processing. Here, the key host player, the cytosolic histone deacetylase 6 (HDAC6), senses misfolded protein 'tags' and activates a cellular pathway that helps to break apart the viral shell during entry. In this study we will address the interplay between HDAC6 and ubiquitin-modifying enzymes, and target multiple host factors to block viral uncoating and thus block infectivity. Our findings may contribute to the understanding of general viral uncoating pathways and lead to conceptualisation of a broad spectrum antiviral that can combat emerging and re-emerging viruses of medical importance.