Tricking the herpes virus out of “hiding”


Herpes is a huge health problem. Twenty million to 30 million Americans have recurrent genital herpes outbreaks, and 700,000 new genital herpes simplex virus infections occur every year. More than 2,000 babies are born with a herpes infection annually, even though 40,000 caesarians are performed due to a fear of transmitting herpes from mother to child.

The herpes simplex virus is a complex high-performance engine designed to replicate itself. When it enters a human host, it encounters an army of cellular defense proteins designed to turn off these engines and prevent the virus from multiplying.

But the herpes virus is capable of fighting back. It can shut down attempts by its host to block it. In skin abrasions and cells lining the mouth or genitals of the host, the virus prevails by overcoming the host’s cellular defenses.

Then, after the herpes virus gets past its host’s cellular defenses and begins to multiply, it infects the host’s neurons. Here a different story takes place.

In neurons, the herpes virus allows itself to be silenced by its host’s defenses and lies dormant until it is activated by hormones or stress on the neurons.

While the virus is dormant it is not vulnerable to antiviral drugs, but when the virus is fighting its host’s cellular defenses it is vulnerable. That’s why Bernard Roizman, ScD, Joseph Regenstein Distinguished Service Professor of Virology and Chair of the Viral Oncology Laboratory at the University of Chicago, and his colleagues are focusing their herpes research on the mechanism by which the host silences the virus. Their work is supported by a two-year $581,604 grant from the National Institutes of Health that has allowed them to hire two fulltime employees, one at the postdoctoral level and one technical assistant.


Waking a sleeping giant


The primary health threat posed by the herpes virus occurs when it is reactivated from its dormant state and causes both new lesions in the person who harbors the virus and in others with whom the host comes into contact.

Today, individuals harboring dormant viruses cannot be cured. One approach that might cure herpes, however, is to disrupt the silencing mechanism harbored in the host’s neurons. This would allow the virus to multiply, at which point the virus could be killed by newly designed antiviral drugs.

To achieve this, Roizman and his colleagues need to know the mechanism by which the virus is silenced in neurons. “We know a lot about host’s cellular defenses at the sites of entry into the body,” he says. “Now, our foremost question is whether the same defenses are operating in neurons.”

If the answer is “yes,” the researchers will be able to begin to develop drugs that temporarily disrupt those defenses. “For now, my University of Chicago research associates Haidong Gu, MD, Grace Zhou and Te Du and I are designing mutant test viruses that will act as ‘Trojan’ viruses aimed at elucidating the neurons’ defense mechanism,” Roizman says.






A vaccine for herpes? Researchers discover immune cells that suppress HSV-2 infection | Fox News

A vaccine for herpes? Researchers discover immune cells that suppress HSV-2 infection


Genital herpes is one of the most common types of sexually transmitted infections (STI) in the United States – as well as one of the most frustrating.  Characterized by periodic blisters on the genitals, rectum or mouth, there is currently no cure for the disease, and it can only be managed by antiviral medications which help shorten outbreak periods.

However, a new study may provide hope for those suffering from this STI. Researchers have identified a subtype of immune cells that suppress outbreaks of genital herpes caused by the herpes simplex virus type 2 (HSV-2).

The discovery could lead to a vaccine capable of preventing herpes lesions on people who have already contracted the STI – or in other words, a vaccine that could “clinically cure” an individual of herpes symptoms.

The newly identified T-cells, called CD8αα+ T-cells, reveal a great deal more information about genital herpes than was initially known.  

“What we found was that (these T-cells) are turned on and making all sorts of antiviral substances,” lead author Dr. Larry Corey, an internationally renowned virologist and president and director of the Fred Hutchinson Cancer Research Center in Seattle, Wash., told  “When the virus reactivates, they are the first cells in to contain the virus, and we showed they contain it very well. They can contain it before the virus escapes above the skin.”

Before this study, researchers believed that herpes reactivation was controlled at the ganglion level of the spinal canal area. But by using a technique called laser capture, Corey and his colleagues were able to biopsy and analyze the RNA in pieces of human tissue from the dermal-epidermal junction (DEJ), where the dermis – the outer layer of skin – connects to the epidermis – the layer of tissue just below the skin’s surface.  The team discovered that these CD8αα+ T-cells are located in the DEJ and are responsible for controlling HSV-2 – implying that herpes reactivation is controlled in the skin, not the spine.

Not only did the research team make this significant discovery about the T-cells’ location, they also found that the CD8αα+ T-cells are programmed to remain in the skin surrounding the genitals at all times – making them resident memory T-cells.  The cells’ long-term persistence may explain why patients have asymptomatic recurrences of genital herpes, because the cells are constantly doing “immune surveillance” – always working to find and destroy HSV-2.

“The real implication here is that the way herpes seems to act is that the virus is actually reactivating very frequently,” Corey said.  “The human immune response is containing it most of the time.”

Researchers had originally estimated that herpes reactivated once a month, but the discovery of these ever-present T-cells led Corey and his team to believe the virus actually reactivates once a week or every few days.  So when herpes lesions occur, it is because there were not enough CD8αα+ T-cells to suppress the outbreak, Corey said.

CD8αα+ T-cells were previously known to exist in the gut mucosa, but most of the research on CD8+ T-cells focused on studying them in blood circulation.  Corey and his team were the first to find the phenotype of CD8αα+ T-cells to persist in the skin.  He said that a potential herpes vaccine would focus on increasing these cells in the immune system.

“It gives us a marker by which one can test vaccines,” Corey said.  “A vaccine that will increase the number or function of these cells would be one you would want to develop.  I don’t think there would be any side effects.”

The vaccine could potentially stop individuals from experiencing outbreaks – the times when a person is most contagious.  Generally, a person can only contract HSV-2 infections during sexual intercourse with an infected individual; however, transmission can still occur when the infected individual does not have a visible sore.

According to the Centers for Disease Control and Prevention, 776,000 people in the United States are infected with herpes each year, and one out of six people between the ages of 14 and 49 have genital HSV-2 infection. While this vaccine would not cure those of HSV-2, it could ultimately help stop the spread of this very prevalent STI.

“We think it’s possible to contain,” Corey said.  “It’s a ‘clinical cure.’”




Researchers discover gene that suppresses Herpesviruses:   TLKs


Tousled-like kinases - TLKs - play a key role in the suppression and activation of Herpesviruses.


Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) hide within the worldwide human population. While dormant in the vast majority of those infected, these active herpesviruses can develop into several forms of cancer. In an effort to understand and eventually develop treatments for these viruses, researchers at the University of North Carolina have identified a family of human genes known as Tousled-like kinases (TLKs) that play a key role in the suppression and activation of these viruses.


In a paper published by Cell Host and Microbe on Feb. 13, 2013, a research team led by Blossom Damania, PhD, of the Department of Microbiology and Immunology and member of the UNC Lineberger Comprehensive Cancer Center, found that suppressing the TLK enzyme causes the activation of the lytic cycle of both EBV and KSHV. During this active phase, these viruses begin to spread and replicate, and become vulnerable to anti-viral treatments.


“When TLK is present, these viruses stay latent, but when it is absent, these viruses can replicate” says Damania.

Patrick Dillon, a postdoctoral fellow in Damania’s lab, led the study. Other co-authors included UNC Lineberger members Drs. Dirk Dittmer, Nancy Raab-Traub and Gary Johnson.


KSHV and EBV are blood-borne viruses that remain dormant in more than 95 percent of those infected, making treatment of these viruses difficult. Both viruses are associated with a number of different lymphomas, sarcomas, and carcinomas, and many patients with suppressed immune systems are at risk for these virus-associated cancers.


“The dormant state of these viruses is what makes it so hard to treat these infections and the cancers associated with these infections,” says Damania.


Researchers have known that stimuli such as stress can activate the virus from dormancy, but they do not understand the molecular basis of the viral activation cycle. With the discovery of the link between these viruses and TLKs, Dr. Damania said that researchers can begin to look for the molecular actions triggered by events like stress, and how they lead to the suppression of the TLK enzymes.


“What exactly is stress at a molecular level? We don’t really understand it fully,” says Damania.


With the discovery that TLKs suppresses these viruses, Damania said that the proteins can now be investigated as a possible drug target for these virus-associated cancers. In its normal function in the cell, TLKs play a role in the maintenance of the genome, repairing DNA and the assembly of the chromatin, but there is a lot more to learn about the function of the TLKs, says Damania. One avenue of her lab’s future research will investigate how TLKs function in absence of the virus.


“If we prevent this protein from functioning, and we combine this with a drug that inhibits viral replication, then we could have a target to cure the cell of the virus. If the virus isn’t there, the viral-associated cancers aren’t present,” says Damania.


Tousled-like kinases



Straitjacket drug halts herpes virus's escape stunt


"You don't ever get the virus coming back,"


As anyone who suffers from recurrent cold sores knows, herpes is a master escapist. This family of viruses – including strains that cause lesions on the genitals, infectious mononucleosis (glandular fever) and, in some cases, blindness and birth defects – is able to wriggle free of the body's defences, reactivating after lying dormant for long periods. Now a new drug that denies the virus its means of escape could lead to treatments that keep herpes locked up for good.


When the virus infects cells, the body defends itself by wrapping up the viral genome in a structure that blocks its genes from being expressed. The virus can escape this straitjacket, though, by hijacking some of the cell's own enzymes to unwrap itself. Once freed, the virus takes hold and spreads.


Thomas Kristie at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and colleagues have developed a drug that inhibits the enzymes the virus uses to free itself – stopping it from escaping. "The virus becomes silent," says Kristie.


The team tested their treatment on mice infected with herpes simplex type 1, which causes lesions on the mouth and eye.

About a month after infection, once the virus had entered its dormant stage, the researchers removed neurons from a brain region behind the eye where herpes lurks, and cultured the cells. They found they were unable to reactivate the virus. "You don't ever get the virus coming back," says Kristie. The drug also appears to limit the spread of the initial infection.


New drug arena


This approach of inhibiting the enzyme that the virus hijacks could lead to new treatments that shut down the herpes family of viruses at an early stage of infection. It might even work on other viruses that take over cells in a similar way, such as HIV. "This could open up a new arena of antiviral drugs that hit a number of viruses," says Kristie.


"It's neat that they got such a potent effect," says Robert White at Imperial College London, UK, who was not involved in the study. But more work is needed to investigate possible side effects, he says, since the drug is likely to be knocking out more than just the host enzymes used by the virus. "It's a bit of a sledgehammer."


A vaccine for herpes? Researchers discover immune cells that suppress HSV-2 infection | Fox News