Epigenetic drugs against human DNA viruses and retroviruses

Epigenetic drugs offer an attractive strategy against DNA viruses and retroviruses that establish chronic infections mimicking the chromatinized host genome. Direct-acting antiviral (DAA) drugs that inhibit viral replication decrease viremia. However, they fail to eradicate the nuclear reservoirs of viral DNA that masquerade as host chromatin, which enable viral genome maintenance and reactivation with possible severe clinical sequelae. Owing to the strides in basic epigenetic and translational research endeavors, we enter a new era of drug development against infections with persistent or latent DNA virus and retroviruses including drugs that target the host epigenetic mechanisms hijacked by the viruses. Epigenetic drugs modulate the virus-host arms race, fortifying host defenses by remodeling the epigenetic landscape inside cells, silencing persistent viral genomes, or inducing massive simultaneous reactivation of latent reservoirs in the presence of DAA. This review aims to highlight the successes, progress, and challenges of this approach by analyzing the emerging preclinical and clinical studies of epigenetic drugs against the retroviruses human immunodeficiency virus (HIV) and human T-cell lymphotropic virus-1 (HTLV-1), the pararetrovirus hepatitis B virus (HBV), and the herpesviruses.