Strain-dependent restriction of human cytomegalovirus by zinc finger antiviral proteins

Lista, M. J. et al. (2023) Strain-dependent restriction of human cytomegalovirus by zinc finger antiviral proteins. Journal of Virology, 97(3), e0184622. (doi: 10.1128/jvi.01846-22) (PMID:36916924) (PMCID:PMC10062169)

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Cellular antiviral factors that recognize viral nucleic acid can inhibit virus replication. These include the zinc finger antiviral protein (ZAP), which recognizes high CpG dinucleotide content in viral RNA. Here, we investigated the ability of ZAP to inhibit the replication of human cytomegalovirus (HCMV). Depletion of ZAP or its cofactor KHNYN increased the titer of the high-passage HCMV strain AD169 but had little effect on the titer of the low-passage strain Merlin. We found no obvious difference in expression of several viral proteins between AD169 and Merlin in ZAP knockdown cells, but observed a larger increase in infectious virus in AD169 compared to Merlin in the absence of ZAP, suggesting that ZAP inhibited events late in AD169 replication. In addition, there was no clear difference in the CpG abundance of AD169 and Merlin RNAs, indicating that genomic content of the two virus strains was unlikely to be responsible for differences in their sensitivity to ZAP. Instead, we observed less ZAP expression in Merlin-infected cells late in replication compared to AD169-infected cells, which may be related to different abilities of the two virus strains to regulate interferon signaling. Therefore, there are strain-dependent differences in the sensitivity of HCMV to ZAP, and the ability of low-passage HCMV strain Merlin to evade inhibition by ZAP is likely related to its ability to regulate interferon signaling, not the CpG content of RNAs produced from its genome.

Item Type:Articles
Additional Information:This work was supported by a St George’s, University of London, Institute of Infection & Immunity Research Support Grant (B.L.S.), Medical Research Council grants MR/S000844/1 (S.J.D.N., C.M.S.), MR/W018519/1 (S.J.D.N., C.M.S.), MC_UU_12014/3 (A.J.D.), MR/W025647/1 (M.P.W.), and MR/S00971X/1 (R.J.S.), plus a Wellcome Trust Senior Research Fellowship (WT098049AIA) (S.J.D.N.).
Glasgow Author(s) Enlighten ID:Nichols, Mrs Jenna and Davison, Professor Andrew
Authors: Lista, M. J., Witney, A. A., Nichols, J., Davison, A. J., Wilson, H., Latham, K. A., Ravenhill, B. J., Nightingale, K., Stanton, R. J., Weekes, M. P., Neil, S. J. D., Swanson, C. M., and Strang, B. L.
College/School:College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:Journal of Virology
Publisher:American Society for Microbiology
ISSN (Online):1098-5514
Published Online:14 March 2023
Copyright Holders:Copyright © 2023 Lista et al.
First Published:First published in Journal of Virology 97(3): e0184622
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172630003Persistent Infections (Programme 2)Andrew DavisonMedical Research Council (MRC)MC_UU_12014/3III - Centre for Virus Research