A Vision for Better Therapy

An estimated 90% of the world’s population is seropositive, unknowingly harboring a potentially dangerous fugitive within their nervous systems. While this intruder typically presents as a minor annoyance, it also has the potential to be debilitating or even deadly.

The enemy within is the incurable and highly successful Herpes Simplex Virus (HSV), which in most people never causes anything worse than an occasional cold sore, but in others, can do damage leading to blindness or even dangerous inflammation of the brain or spinal cord, a frequently fatal condition. Globally, 1 million new cases and 9 million cases of recurrent infection occur yearly.

There are two types of HSV, designated HSV-1 and HSV-2, both of which can result in a diverse range of symptoms and pathology that can lead to lifelong complications. While active manifestations of HSV-1, such as cold sores, are treatable, once contracted, the virus remains in the host’s nervous system in an inactive state, ready to reemerge when certain conditions are favorable. “Asymptomatic cases of HSV are also extremely common,” according to the National Institutes of Health (NIH) Strategic Plan for Herpes Simplex Virus Research, “and those who are asymptomatic continue to shed the virus and can transmit it to close contacts.

“Once in the host,” the Plan continues, “the virus can then transition to a quiescent state, called latency, actively suppressing the expression of genes that could lead to detection by the human immune system. In this manner, the virus can exist for extended periods of time in the body without causing symptoms. Once a ‘trigger’ for transition out of latency occurs, HSV reverts into its active, or lytic state. Known triggers for virus reactivation include stress, sunlight, immune suppression, and a variety of other factors.”

It is exactly because HSV is such a successful pathogen and worthy opponent that    Dr. Amol Suryawanshi, an associate professor of immunology in the Department of Pathobiology at the Auburn University College of Veterinary Medicine, first decided to research it while beginning his doctorate studies at the University of Tennessee. “I earned my DVM in India, but determined I was more interested in research than the practice side,” he recalled. “I became interested in HSV because it is so widespread and also because it is such a successful pathogen. There is no vaccine for it and the current treatments can have a variety of unwanted side effects.”

Those are the same reasons the NIH has made HSV research an area of major emphasis. “Although HSV is extremely common worldwide, considerable gaps remain in the fundamental understanding of [the viruses],” the Plan further noted. “NIH will continue to support research … toward understanding the basic biology of the HSV viruses that will accelerate advances in diagnostics, vaccine development and efforts towards a cure.” Suryawanshi, who joined the Auburn faculty in 2008, is part of those efforts, along with his research team of Auburn CVM graduate students, including Ferrin Anthony, Chetan Pundkar, Jiayi Ren and Gurjinder Kaur. Suryawanshi was recently awarded two five-year grants from the NIH — one for $1,932,636 to study immunoregulation of SK and a second for $453,296 to examine targeted antiviral and anti-inflammatory responses — that will allow him and the team to pursue his HSV studies further. Specifically, he is looking at ways to manipulate the immune system to combat an eye condition called Herpes Simplex Keratitis (SK). This recurrent corneal HSV-1 infection is the leading infectious cause of corneal ulcers and blindness worldwide.

“When a person is infected with the virus and gets a cold sore, the immune system kicks in,” Suryawanshi explained. “The cold sore may resolve, but the virus infiltrates the neurons and invades the nervous system. Once there, it stays in a latent form for the rest of that person’s life. If conditions are right it can enter the eyes, where it replicates in the cornea. And a cold sore in the cornea is not a good thing.”

In fact, it can be a very bad thing. SK causes increasing opacity of the cornea similar to that brought on by a cataract, plus severe inflammation of the blood vessels in the eye, further degrading vision. If left untreated, it can eventually cause blindness. Current SK treatment involves both antivirals and anti-inflammatories, but because the virus resides within the nervous system, the medications must be delivered orally in large dosages to be effective. And such large amounts of both have their own downsides, mainly in the form of undesirable side effects.

In addition, current therapies are aimed only at active virus infections and have no effect on the latent HSV lurking in the nervous system that lies behind them. Treating the symptoms without eliminating the underlying cause is a temporary solution at best. For that reason, Suryawanshi and his research team are looking at a different approach to battle SK. “We are working on how to control the virus by manipulating the patient’s own immune system,” he said. “Our ultimate goal is to find a therapy that will control both viral replication and the inflammation that results.”

That therapy may ultimately lie in a cytokine — or protein such as interferon — secreted by the cells of the immune system, called macrophages. This particular cytokine, dubbed IL-27, has shown promise against HSV, but after an infection begins, IL-27 production is suppressed, reducing the effectiveness of the immune response. “We don’t know why that occurs,” Suryawanshi noted. “But it is one of the things we are seeking to understand with our research.”

Discovering a way to stimulate IL-27 production by the macrophages of the immune system may hold promise, but just as the current treatments have negative side effects, the manipulation of the immune system comes with its own set of risks. “Macrophages are both good and bad,” cautioned Suryawanshi. “They kill a virus by causing lots of damage to its cellular structure, but once the virus is successfully contained, the macrophages themselves need to be restrained. So there is always a delicate balance between damage and suppression. Finding that balance is another goal of our research. But the ultimate goal is to learn more about how HSV has been so successful so we can devise better ways to defeat it.”