Liang Y, Vogel JL, Arbuckle JH, Rai G, Jadhav A, Simeonov A, Maloney DJ, Kristie TM. Targeting the JMJD2 Histone Demethylases to Epigenetically Control Herpesvirus Infection and Reactivation from Latency. Sci Transl Med. 2013 Jan 9. PMID: 23303604.
Common Infections..Sometimes Uncommon Effects
Herpesviruses are fundamentally different from most other viruses we come into contact with. Most viruses get completely eliminated from our systems but herpesviruses have found a way to stick around – usually effectively bottled up by our immune system – for a lifetime ride in our cells. Very common in humans, we’ve all been exposed to and almost all of us carry a latent or inactive herpesvirus infection.
Usually contracted in childhood most herpesvirus infections produce nothing more troubling than a childhood cold but they have a dark side. A Epstein Barr virus infection that causes a mild cold in childhood often produces infectious mononucleosis in adolescents and increase one’s risk of later coming down with multiple sclerosis and ME/CFS. A mild herpes simplex infection during childhood can turn into an painful case of shingles when we’re older.
Herpesvirus infections may be ubiquitous and usually mild but they can cause encephalitis, blindness, horrific neurological problems and inflammation if they hit the right person at the wrong time. Not surprisingly, people with impaired immune systems such transplant patients are at high risk of herpesvirus reactivation with sometimes deadly consequences.
Key Viruses in Chronic Fatigue Syndrome (ME/CFS)
Herpesviruses may play a key role in ME/CFS as well. How many people with chronic fatigue syndrome have a reactivated form of the virus is still unclear but some doctors believe the percentage is substantial. Many people begin their experience with chronic fatigue syndrome (ME/CFS) with a herpesvirus infection in the form of infectious mononucleosis.
Dr. Lerner and Dr. Glaser believe an unusual form of Epstein-Barr virus is wreaking havoc in many patients. Their model suggests proteins and enzymes produced by a partial reactivation of the virus are sending the immune system into a tizzy and causing fatigue and other symptoms. Because the current slate of herpesvirus antivirals attack the virus in the later stages of it’s development they’re in effect missing the action in ME/CFS. These drugs work to some degree. As they slowly lower viral load, the cells harboring the viruses die off over time.
“there remains a clear need to develop new antivirals”
The problem is that in this model the road to recovery takes time and lots of it; often a year or more of taking expensive antivirals. Dr. Lerner’s been looking for a treatment that will hit the virus just as it’s starting to replicate and he’s not alone. Even when the full virus is present, the present slate of antivirals still sometimes arrive too late to prevent blindness, neurological problems, birth defects and inflammation. The current herpesvirus antivirals come too late to the scene to
- block the production of mutant viruses that can give rise to resistant strains of virus
- block the expression of early viral enzymes that effect and can produce cancer in cells
- block the product of viral proteins that can trigger a damaging immune response (Lerner/Glaser’s theory of ME/CFS)
A Possible Breakthrough
“Depletion of the JMJD2 members or inhibition of their activity with a new drug results in repression of expression of viral immediate early genes and abrogation of infection. This inhibitor also represses the reactivation of HSV from the latent state in sensory neurons”
That may be changing. Researchers working at National Chemical Genomic Center (NCGC) have a developed a ‘probe’ that stops herpesviruses from replicating by pouncing on the early enzymes they use to build a new virus. (Ironically the virus uses our genetic machinery to get our bodies to produce the enzymes to build another virus). These researchers were able to design this probe after they figured out what genes these herpesviruses activate early in their life cycle. This ‘epigenetic’ approach – stopping a virus by targeting the genes it needs to replicate – may very well herald a new era in antiviral therapy.
It’s death by small cuts. By continually stopping the virus from replicating the herpesvirus will eventually die when the cell they’re living in dies. The good news for ME/CFS patients is that this probe could also whack the very enzymes Lerner and Glaser believe are causing ME/CFS. That could mean no more long, expensive and sometimes dangerous treatment regimens.
The Implications for Chronic Fatigue Syndrome (ME/CFS)
This study focused on two herpesvirus infections (cytomegalovirus (HCMV), herpes simplex) sometimes found in ME/CFS. In Dr. Peterson’s presentation in Paris on the successful treatment of HCMV infections in ME/CFS, he reported that a small subset of ME/CFS patients have an active herpes simplex infection, as did Dr. Montoya at the FDA Drug Development Workshop.
Epstein-Barr Virus and Human Herpesvirus 6?
Continued elucidation of the mechanisms and components involved in epigenetic regulation of viral pathogens will lead to additional targets for antiviral development
Epstein-Barr Virus (EBV) and Human Herpesvirus 6 (HHV6) are the pathogens most commonly associated with ME/CFS, however. I was unable to determine if the enzyme targeted by this probe is found in these viruses. The fact that the herpesvirus family undergoes a process called chromatic assembly and modulation in which the enzyme plays a role suggests the probe might be effective in other herpesviruses.The fact that the probe worked in both alpha and beta herpesviruses (EBYis a gamma herpesvirus) suggests it may have widespread application but we’ll have to see if it applies to these viruses as well.
Dr. Martin Lerner, a specialist in treating herpesvirus infections in chronic fatigue syndrome has high hope for this approach.
My own research suggest immediate early gene products initiate CFS. I think this work has great promise in effectively inhibiting many herpesviruses. Dr. Martin Lerner
Even if it doesn’t this discovery provides a new approach to drug treatment that could be duplicated in other herpesviruses. Indeed these researchers are already looking for other epigenetic targets, one of which is found in Epstein-Barr virus.
This ‘probe’ has still long way to get to the marketplace. It’s demonstrated its effectiveness in cultured cells and now needs to be assessed in animal models and humans.
A New Paradigm for Antiviral Drug Development
There is intensive focus on the development of inhibitors of epigenetic components for the treatment of cancers and other diseases. The study presented here demonstrates that epigenetic inhibitors can also function as antiviral therapeutic agents.
The success of a drug employing a epigenetic approach to infection was big news with the study appearing in the premier scientific journal Science and the authors urging other researchers to pour resources into developing more epigenetic tools to fight infection.