Transient activation of human cytomegalovirus lytic gene expression during latency allows cytotoxic T cell killing of latently infected cells.
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Krishna, B., Lau, B., Jackson, S., Wills, M., Sinclair, J., & Poole, E. (2016). Transient activation of human cytomegalovirus lytic gene expression during latency allows cytotoxic T cell killing of latently infected cells.. Sci Rep, 6 (24674) https://doi.org/10.1038/srep24674
Human cytomegalovirus (HCMV) latency in the myeloid lineage is maintained by repressive histone modifications around the major immediate early promoter (MIEP), which results in inhibition of the lytic viral life cycle. We now show that pharmacological inhibition of histone deacetylases (HDACs) relieves this repression of the MIEP and induces transient expression of the viral lytic immediate early (IE) antigens but, importantly, not full virus reactivation. In turn, these latently infected cells now become targets for IE-specific cytotoxic T cells (CTLs) which are present at high frequency in all normal healthy HCMV positive carriers but would normally be unable to target latent (lytic antigen-negative) cells. This approach of transiently inducing viral lytic gene expression by HDAC inhibition, in otherwise latently infected cells, offers a window of opportunity to target and purge the latent myeloid cell reservoir by making these normally immunologically undetectable cells visible to pre-existing host immune responses to viral lytic antigens.
This work was funded by a British Medical Research programme grant, grant number G0701279 and Wellcome Research Grant, grant number RG68483. This research was supported by the Cambridge NIHR BRC Cell Phenotyping Hub.
Medical Research Council (G0701279)
Medical Research Council (MR/K021087/1)
MRC (MC_PC_14116 v2)
External DOI: https://doi.org/10.1038/srep24674
This record's URL: https://www.repository.cam.ac.uk/handle/1810/255121
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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