Herpesvirus latency

Abstract

Herpesviruses infect virtually all humans and establish lifelong latency and reactivate to infect other humans. Latency requires multiple functions: maintaining the herpesvirus genome in the nuclei of cells; partitioning the viral genome to daughter cells in dividing cells; avoiding recognition by the immune system by limiting protein expression; producing noncoding viral RNAs (including microRNAs) to suppress lytic gene expression or regulate cellular protein expression that could otherwise eliminate virus-infected cells; modulating the epigenetic state of the viral genome to regulate viral gene expression; and reactivating to infect other hosts. Licensed antivirals inhibit virus replication, but do not affect latency. Understanding of the mechanisms of latency is leading to novel approaches to destroy latently infected cells or inhibit reactivation from latency.

Figure 1. Features of herpesvirus latency.

(A and B) Latent herpesvirus genomes are maintained in the nuclei of cells as circular episomes (A) and in dividing cells the viruses express proteins during cell division that partition the episomes to daughter cells (B). (C) Alphaherpesviruses encode long noncoding viral RNAs during latency that are transcribed antisense to viral genes expressed during lytic infection. (D) Latent herpesvirus DNA genomes are associated with histone proteins; genes normally expressed during virus lytic replication are silenced by methylation or other modifications of their histone tails during latency. (E) Chromatin insulators containing DNA sequences and the corresponding DNA-binding proteins and chromatin-modifying proteins act to separate regions of active euchromatin and repressed heterochromatin to regulate latency. (F) Herpesvirus microRNAs (miRNAs) produced during latency degrade or inhibit expression of virus lytic genes or host cell genes.

Figure 2. New approaches to killing latently infected cells or inhibiting reactivation from latency.

(A) Herpesvirus-specific endonucleases cleave viral DNA, and DNA repair enzymes rejoin the DNA that can result in inability to maintain latency or reactivate from latency. (B) Treatment of EBV latently infected cells with bortezomib or histone deacetylase (HDAC) inhibitors activates virus replication and production of the viral protein kinase, which phosphorylates ganciclovir, resulting in cell death (panel adapted with permission from ref. . © the American Society of Hematology). (C) Supplemental glutamine increases IFN-γ–producing HSV-specific T cells that reduce virus reactivation from ganglia. (D) Inhibition of histone methyltransferase or histone demethylase converts euchromatin to repressed heterochromatin and reduces immediate-early gene expression to inhibit reactivation. Glanciclovir, GCV; glanciclovir monophosphate, GCV-P; glanciclovir triphosphate, GCV-PPP; protein kinase, PK.