Transient activation of human cytomegalovirus lytic gene expression during latency allows cytotoxic T cell killing of latently infected cells.
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.
Department of Medicine, University of Cambridge, Level 5 Laboratories Block, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ.
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Krishna
Department of Medicine, University of Cambridge, Level 5 Laboratories Block, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ.
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Lau
Department of Medicine, University of Cambridge, Level 5 Laboratories Block, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ.
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Jackson
Department of Medicine, University of Cambridge, Level 5 Laboratories Block, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ.
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Wills
Department of Medicine, University of Cambridge, Level 5 Laboratories Block, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ.
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Sinclair
Department of Medicine, University of Cambridge, Level 5 Laboratories Block, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ.
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Poole
D018920:Coculture Techniques; D003587:Cytomegalovirus / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D017735:Virus Latency
D056572:Histone Deacetylase Inhibitors