Research ArticlesInfectious Disease

Targeting the JMJD2 Histone Demethylases to Epigenetically Control Herpesvirus Infection and Reactivation from Latency

Science Translational Medicine  09 Jan 2013:
Vol. 5, Issue 167, pp. 167ra5
DOI: 10.1126/scitranslmed.3005145

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Keeping Herpesviruses Under Wraps

Despite the pharmaceuticals currently used to control herpesvirus infections and recurrences, herpes simplex virus and its cousin human cytomegalovirus remain important medical pathogens that are responsible for a high incidence of herpetic blindness, complications during organ transplant, and birth defects. In addition, antiherpetic drugs target a late stage in viral infection, allowing drug-resistant viral strains to escape, and resulting in tissue damage from immune-mediated inflammation and subclinical shedding of infectious virus particles.

A big goal is to develop drugs that both target the very early events in viral infection and prevent reactivation of the virus from its latent state. Upon infection of a cell with herpes simplex virus or human cytomegalovirus, the cell suppresses the expression of the first class of viral genes by wrapping the viral genome in a type of repressive nucleosomal structure that the cell uses to silence its genes. These viruses, however, have evolved in their ability to commandeer the cellular enzymatic machinery to reverse this repressive packaging, allowing the expression of the viral genes and initiation of productive infection.

Identification of the specific enzymes required by these two viruses led Liang et al. to isolate a new inhibitor that blocked the “unwrapping” of the viral genomes. This compound potently suppressed infection of cultured cells with herpes simplex virus or human cytomegalovirus and suppressed the reactivation of herpes simplex virus from latency in a mouse model. Inhibitors such as the compound described in the Liang et al. study represent a new approach to suppressing early events in viral infection that may prevent the rise of resistant viral strains, limit damaging inflammation, and block viral shedding and transmission.