Control of viral infections by epigenetic-targeted therapy

Abstract

Epigenetics is defined as the science that studies the modifications of gene expression that are not owed to mutations or changes in the genetic sequence. Recently, strong evidences are pinpointing toward a solid interplay between such epigenetic alterations and the outcome of human cytomegalovirus (HCMV) infection. Guided by the previous possibly promising experimental trials of human immunodeficiency virus (HIV) epigenetic reprogramming, the latter is paving the road toward two major approaches to control viral gene expression or latency. Reactivating HCMV from the latent phase ("shock and kill" paradigm) or alternatively repressing the virus lytic and reactivation phases ("block and lock" paradigm) by epigenetic-targeted therapy represent encouraging options to overcome latency and viral shedding or otherwise replication and infectivity, which could lead eventually to control the infection and its complications. Not limited to HIV and HCMV, this concept is similarly studied in the context of hepatitis B and C virus, herpes simplex virus, and Epstein-Barr virus. Therefore, epigenetic manipulations stand as a pioneering research area in modern biology and could constitute a curative methodology by potentially consenting the development of broad-spectrum antivirals to control viral infections in vivo.

Keywords: Cancer; Epigenetics; HCMV; HIV; Treatment; Virus.

Fig. 1

Epigenetic manipulation to eradicate HIV: “shock and kill” or “block and lock”? a Latent HIV provirus-established reservoirs in infected resting CD4+ memory T cells and myeloid cells are not eliminated by cART and are thus prone to be reactivated after cART discontinuation. One strategy to eliminate those reservoirs is the “shock and kill” therapy. b Shock-inducer agents like histone deacetylase (HDAC), DNA, or histone methyltransferase (DNMT and HMT respectively) inhibitors used alone or in combination with other players (PKC agonists, P-TEFb releasing agents, TNF, TPA) could reverse latency through the removal of repressive silencing marks imposed on the nucleosome Nuc-1 or the DNA. This purges the viral reservoirs and leads eventually to the clearance of virus-harboring cells along with cART. On the other hand (c), blocking Tat, a viral protein indispensable for the recruitment of transcriptional factors like the positive transcription elongation factor B (P-TEFb), by a latency inducing reagent such as dCA reduces viral transcription and locks the HIV promoter in a super-latency state resistant to any reactivation stimuli leading potentially to a functional cure

Fig. 2

Schematic representation of the interplay between HCMV and epigenetic players in the context of lytic and latent infection. a During lytic infection, the repressive marks silencing the major immediate-early promoter (MIEP) are rapidly overcome, which results in the expression and transcription of the immediate early (IE) proteins. Histone demethylase (HDM) inhibitors can reverse and block viral activation at an early stage of infection, as well as during viral reactivation. b During latency, the repressive inhibition of the MIEP could be reversed by the polycomb complex 2 (PRC2) inhibitors or chloroquine, considered as latency reversal agents. The activated transcriptional program could purge the viral reservoirs (shock) and possibly achieve a sterilizing cure (kill) along with antivirals treatment. Alternatively, histone deacetylase (HDAC) inhibitors might induce a transient viral antigen expression, the latter being a target for pre-existing IE-specific cytotoxic T lymphocytes (CTL)