Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency.
Krishna, Benjamin A
Lim, Eleanor Y
Sedikides, George X
American Society for Microbiology
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Elder, E., Krishna, B. A., Williamson, J., Lim, E. Y., Poole, E., Sedikides, G. X., Wills, M., et al. (2019). Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency.. mBio, 10 (6)https://doi.org/10.1128/mbio.02574-19
Human cytomegalovirus (HCMV) latency is an active process which remodels the latently infected cell to optimise latent carriage and reactivation. This is achieved, in part, through the expression of viral genes, including the G-protein coupled receptor US28. Here, we use an unbiased proteomic screen to assess changes in host proteins induced by US28, revealing that interferon-inducible genes are downregulated by US28. We validate that MHC Class II and two PYHIN proteins, MNDA and IFI16, are downregulated during experimental latency in primary human CD14+ monocytes. We find that IFI16 is targeted rapidly during the establishment of latency in a US28-dependent manner, but only in undifferentiated myeloid cells, a natural site of latent carriage. Finally, by overexpressing IFI16, we show that IFI16 can activate the viral major immediate early promoter and immediate 2 early gene expression during latency via NF-κB, a function which explains why downregulation of IFI16 during latency is advantageous for the virus.
Monocytes, Cell Line, Myeloid Cells, Humans, Cytomegalovirus, Cytomegalovirus Infections, NF-kappa B, Interferons, Receptors, G-Protein-Coupled, Viral Proteins, Proteomics, Virus Latency, Virus Activation, Cell Differentiation, Gene Expression, Down-Regulation, Gene Expression Regulation, Viral, Promoter Regions, Genetic, HEK293 Cells, THP-1 Cells
This work was funded by the British Medical Research Council, Grant (Grant G0701279), the Wellcome Trust (Grant 109075/Z/15/A) and the Cambridge NIHR BRC Cell Phenotyping Hub.
WELLCOME TRUST (109075/Z/15/Z)
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External DOI: https://doi.org/10.1128/mbio.02574-19
This record's URL: https://www.repository.cam.ac.uk/handle/1810/298846
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