NIH Scientists Develop Promising Herpesvirus Drug Candidate

NIH Scientists Develop Promising Herpesvirus Drug Candidate
 

NIH Scientists Develop Promising Herpesvirus Drug Candidate

Blocks Infection and Reactivation in Mice

Scientists at the National Institute of Allergy and Infectious Diseases (NIAID) and National Center for Advancing Translational Sciences, two components of the National Institutes of Health (NIH), have identified key proteins required by two different herpesviruses to initiate infection. Based upon these findings, the groups demonstrated that inhibiting the activities of these proteins with a novel drug blocks herpesvirus infection and reactivation from dormancy.

Sensory ganglia from mice latently infected with herpes simplex virus-1 are stained for reactivating virus. At left, the large red neuron illustrates reactivating virus, and surrounding smaller red cells show the spread of infection from the neuron to support cells. At right, a novel inhibitor, ML324, blocks the virus from reactivating (absence of large red neurons). Credit: NIAID

Background

Eight herpesviruses are known to infect humans. They include herpes simplex virus (HSV) types 1 and 2, which cause oral and genital herpes, and human cytomegalovirus (HCMV), which can cause significant complications in immune-compromised people, such as organ transplant recipients who take anti-rejection drugs. HCMV also is the leading viral cause of birth and developmental defects.
Like all members of the herpesvirus family, these viruses establish life-long dormant infections in people and can reactivate at any time to cause disease.
When a herpesvirus infects a cell, its DNA is wrapped into histone-protein structures, called nucleosomes, that can either enhance or repress the initial stage of infection. Building on work published in 2009, the NIH scientists focused on identifying the cellular enzymes required to prevent these structures from repressing viral gene expression, thus allowing infection to proceed.

Results of Study

The scientists demonstrated that during the early stages of infection, HCMV and HSV-1 require two classes of host enzymes, called LSD1 and JMJD2, to modify the histone structures and activate the first wave of viral gene expression. Depleting either of these host enzymes repressed HSV-1 and HCMV infection. 
In the previous work, NIAID scientists demonstrated that inhibiting LSD1 using a type of anti-depression drug called an MAO inhibitor blocked HSV-1 infection. Therefore, they tested synthetic small-molecule compounds to identify a drug that would inhibit the second group of enzymes, the JMJD2 family. The researchers found that one of these compounds, designated ML324, blocked the infection of HSV-1 or HCMV; blocked the spread of infection when used post-exposure; and blocked the reactivation of HSV-1 from latency in a mouse model.

Significance

Most anti-herpetic treatments used today target late-stage infection. While these drugs are an important advance in the treatment of herpesvirus infections, they do not prevent early-stage infection, which can result in inflammation and tissue damage. These drugs also do not efficiently prevent the transmission of virus to others. In contrast, targeting the initiation stage of infection may prove to be more effective in controlling infection-related tissue damage and transmission. This NIH study provides additional evidence in support of emerging therapeutic strategies that aim to modulate human host proteins to fight infections.
Importantly, as these and potentially other related viruses use common enzymes to initiate infection, such as LSD1 and JMJD2, the novel inhibitors in this study may have the capacity to treat other viral infections.

Next Steps

The scientists are continuing their studies of ML324 in animal models of infection and viral reactivation from latency. Additionally, they are investigating other required host proteins that may also serve as potential targets for antiviral development.

References

Y Liang et al. Targeting the JMJD2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency. Science Translational Medicine DOI: 10.1126/scitranslmed.3005145, (2013).
Y Liang et al. Inhibition of the histone demethylase LSD1 blocks α-herpesvirus lytic replication and reactivation from latency. Nature Medicine DOI: 10.1038/nm.2051, (2009).