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Title: Investigating the ability of host factors to restrict influenza A viruses
Author: Vaughan, Aisling Marie
ISNI:       0000 0004 9356 6539
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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To replicate successfully, an invading virus must avoid restriction executed by a multitude of host cell intrinsic factors and interferon stimulated genes (ISGs). While the roles of a number of key antiviral proteins have been delineated, the majority of these factors remain largely uncharacterized. In this study, a number of intrinsic and interferon inducible host factors were assessed for their ability to restrict influenza A replication. Three specific factors were studied in detail that inhibited replication at entry, polymerase activity and exit. Ly6E, a glycosylphosphatidylinositol (GPI)-anchored, interferon-inducible protein was found to target an early, post-entry stage of influenza A replication. Overexpression of Ly6E inhibited virus infection, and decreased the expression of reporter viral-like RNA when driven by infecting virus, but not when driven by polymerase components reconstituted in situ. Ly6E was found to modulate interferon signaling. These results are consistent with published data, which point to a role of this GPI-linked in cell signaling and suggest that Ly6E is a negative regulator of the IFN response. Taken together the results show Ly6E to be an antiviral and proviral factor, a duality that has been observed for other host factors. GBP3, an interferon inducible member of the guanylate binding protein family, was also found to inhibit virus replication when overexpressed. This protein inhibited the reconstituted viral polymerase derived from avian influenza viruses more efficiently than those cloned from human adapted viruses suggesting adaptation of avian viruses to species mammalian may involve strategies to avoid this antiviral factor. Finally, the ability of the SERINC family to inhibit influenza A virus was investigated. Unlike other host factors studied in this thesis, the members of this family of multipass transmembrane proteins are not induced by interferon. However, they are of significant interest as they have previously been shown to inhibit HIV-1 infectivity when incorporated into virions. We found that overexpression of SERINC2, 3 and 5 inhibited replication of influenza A and that expression of MLV GlycoGag (known to counter SERINC activity) rescues this restriction. Interestingly, we observed a reduction in particle number rather than infectivity of particles produced in SERINC expressing cells. These data suggest that the SERINC proteins may function to restrict other viruses outside of their published roles in the inhibition of retroviruses. Taken together this study highlights the ability of human host factors to affect multiple steps in the influenza A virus replication cycle, and broadens our understanding of the complex interplay between influenza A virus and the host.
Supervisor: Barclay, Wendy Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral