Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes

Abstract

The high prevalence of Herpesviruses in the population and the maintenance of lifelong latent reservoirs are challenges to the control of herpetic diseases, despite the availability of antiviral pharmaceuticals that target viral DNA replication. In addition to oral and genital lesions, herpes simplex virus infections and recurrent reactivations from the latent pool can result in severe pathology including neonatal infection and mortality, blindness due to ocular keratitis, and viral-induced complications in immunosuppressed individuals. Herpesviruses, like their cellular hosts, are subject to the regulatory impacts of chromatin and chromatin modulation machinery that promotes or suppresses gene expression. The initiation of herpes simplex virus infection and reactivation from latency is dependent on a transcriptional coactivator complex that contains two required histone demethylases, LSD1 and JMJD2s. Inhibition of either of these enzymes results in heterochromatic suppression of the viral genome and a block to infection and reactivation in vitro. Here, the concept of epigenetic suppression of viral infection is demonstrated in three animal models of herpes simplex virus infection and disease. Inhibition of LSD1 via treatment of animals with the monoamine oxidase inhibitor tranylcypromine results in suppression of viral lytic infection, subclinical shedding, and reactivation from latency in vivo. Phenotypic suppression is correlated with enhanced epigenetic suppression of the viral genome and suggests that, even during latency, the chromatin state of the virus is dynamic. Given the expanding development of epipharmaceuticals, this approach has substantial potential for anti-herpetic treatments with distinct advantages over the present pharmaceutical options.

Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens

“…Inhibitors of the histone H3K9 demethylases (LSD1, JMJD2) block initiation of HSV infection, while inhibitors of the H3K9 and H3K27 demethylases (UTX/JMJD3) block reactivation from latency. Most strikingly, inhibition of LSD1 in vivo enhances epigenetic repression of the latent HSV genomes, which correlates with a reduction of reactivation and viral shedding (15). Here, treatment of primary cells with EZH2/1 inhibitors suppressed HSV gene expression, decreased the spread of the infection to adjacent cells, and blocked the spread of viral reactivation in latently infected sensory ganglia.…”

“…Thus, components of the cellular epigenetic machinery represent a plethora of novel therapeutic targets that can be used to modulate the expression of specific gene sets and alter the course of disease. Inhibitors of LSD1 and members of the JMJD2 family of histone H3K9 demethylases have been shown to suppress HSV infection and reactivation from latency (15)(16)(17)(18). In a contrasting approach, histone deacetylase inhibitors have been components of some strategies to induce HIV reactivation and deplete latent viral reservoirs (19)(20)(21).…”

Restarting Lytic Gene Transcription at the Onset of Herpes Simplex Virus Reactivation

“…Expression of the L genes is dependent on viral DNA replication, and the stimulatory effect of VP16 is evident. As already mentioned, VP16 is recruited together with host cofactors, such as HCF-1, to the IE promoters and facilitates the recruitment of additional chromatin-remodeling and histone-modifying proteins (29). The requirement for VP16 in phase II argues that chromatin remodeling is critical for full reactivation.…”

“…The requirement for VP16 in phase II argues that chromatin remodeling is critical for full reactivation. Likewise, the activities of cellular H3K27 demethylases (UTX/KDM6A and JMJD3/KDM6B) and the H3K9 demethylase (LSD1/KDM1) are also required for the transition to full reactivation (14,(29)(30)(31). Interestingly, explant reactivation, which involves significant physical trauma (axotomy) to the neurons, produces new virus much faster than reactivation through PI3K inhibition (32).…”

Inhibition of H3K27me3-Specific Histone Demethylases JMJD3 and UTX Blocks Reactivation of Herpes Simplex Virus 1 in Trigeminal Ganglion Neurons

“…H3K27me3 is reversibly removed through the action of specific histone demethylases KDM6B/JMJD3 and KDM6A/ UTX (7). H3K9me3 can be removed by all members of the JMJD2 family (8), while H3K9me2/me3/1 can be removed by LSD1, KIAA1718, JHDM1F, and JMJD1A (9)(10)(11)(12). In this study, we sought to determine whether blocking the removal of H3K27me3 would also block HSV-1 reactivation.…”