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Latency-associated expression of human cytomegalovirus US28 attenuates cell attenuates cell signalling pathways to maintain latent infection

Published version
Peer-reviewed

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Authors

Sinclair, JH 
Krishna, Benjamin Anthony Cates  ORCID logo  https://orcid.org/0000-0003-0919-2961
Smit, M 

Abstract

Reactivation of human cytomegalovirus (HCMV) latent infection from early myeloid lineage cells constitutes a threat to immunocompromised or immune-suppressed individuals. Consequently, understanding the control of latency and reactivation to allow targeting and killing of latently infected cells could have far-reaching clinical benefits. US28 is one of the few viral genes that is expressed during latency and encodes a cell surface G protein-coupled receptor (GPCR), which, during lytic infection, is a constitutive cell-signaling activator. Here we now show that in monocytes, which are recognized sites of HCMV latency in vivo, US28 attenuates multiple cell signaling pathways, including mitogen-activated protein (MAP) kinase and NF-κB, and that this is required to establish a latent infection; viruses deleted for US28 initiate a lytic infection in infected monocytes. We also show that these monocytes then become potent targets for the HCMV-specific host immune response and that latently infected cells treated with an inverse agonist of US28 also reactivate lytic infection and similarly become immune targets. Consequently, we suggest that the use of inhibitors of US28 could be a novel immunotherapeutic strategy to reactivate the latent viral reservoir, allowing it to be targeted by preexisting HCMV-specific T cells.

Description

Keywords

cytomegalovirus, immunotherapy, latent infection, virology

Journal Title

mBio

Conference Name

Journal ISSN

2161-2129
2150-7511

Volume Title

8

Publisher

American Society for Microbiology
Sponsorship
Medical Research Council (MR/K021087/1)
Medical Research Council (G0701279)
Wellcome Trust (099790/Z/12/Z)
This work was funded by the British Medical Research Programme (grant G0701279; J.H.S.), a Wellcome Research Studentship Grant (B.A.K.), and the Cambridge NIHR BRC Cell Phenotyping Hub.