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Virology Research Goes Viral

Drs. Miranda, Verdin, and Ott are advancing our knowledge of viruses and the immune system by doing basic science research, and progress made in one disease often leads to discoveries made in another. [Photo: Chris Goodfellow]

A discovery about a protein involved in HIV may result in a cure for type 1 diabetes.

Understanding how hepatitis C infects the liver could lead to a treatment for Dengue fever.

These are just two examples of the wide-ranging implications of virology research—with revelations about one virus often applying to several others, as well as to normal cell processes.

The commonalities among most viruses means progress with one can propel advances in others, for although they manifest differently, viruses use the same general strategies to subvert the immune system, often targeting different elements of the same cellular processes.

“Research into the basic biology of a virus can have an exponential impact,” says Warner Greene, MD, PhD, director of the Gladstone Institute of Virology and Immunology. “Sometimes, insights with one virus open our understanding of other viruses and the diseases they cause.”

For example, a discovery by Gladstone senior investigators Melanie Ott, MD, PhD, and Eric Verdin, MD, about HIV and the protein sirtuin 1 (SIRT1) has inspired the scientists to create a potential treatment for autoimmune disorders like type 1 diabetes and multiple sclerosis (MS).

SIRT1 is a key regulator of the immune system. When the protein is active, it can help regulate HIV levels. In some cases, however, too much SIRT1 activity can contribute to the development of autoimmune diseases—preventing CD4+ T cells, the so-called “helper” T cells, from turning into the regulatory T cells that stop the immune system from attacking the body.

Using a mouse model of MS, Drs. Ott and Verdin have shown for the first time that suppressing SIRT1 activity can prevent the onset of an autoimmune disorder. By inhibiting the protein, the investigators cleared a path for strong and stable regulatory T cells to develop in the mice. In turn, these T cells succeeded in halting the hyperactive immune response characteristic of the disorder.

Drs. Ott and Verdin believe this method may also prove effective in treating type 1 diabetes, and they are currently conducting experiments to test their hypothesis. Diabetes is particularly important to the two scientists, whose young son was diagnosed with the disease. “Although we are not working on MS or diabetes all the time, we have been able to use our broader study of SIRT1 to benefit the entire disease class of which these are a part,” notes Dr. Ott.

In another example of how her research extends across disease lines, Dr. Ott has revealed a critical interaction between HCV and lipid droplets, which are responsible for storing fat in the body’s cells. HCV requires these cellular fat deposits to replicate, often causing them to swell in the process. When this swelling occurs in the liver, the primary target of HCV, it can result in an overall fattening of the organ (called steatosis), leading years later to cirrhosis and liver failure. Thus, interrupting HCV’s interaction with lipid droplets could prevent the virus from replicating and causing liver damage. Dr. Ott’s laboratory has recently shown that these same lipid droplets also play a role in the spread of Dengue fever—a disease in the same family as HCV that affects 300 million people around the world each year. Dr. Ott has now begun to apply her knowledge about the interaction between viruses and the droplets to search for a potential Dengue fever treatment.

Gladstone investigator JJ Miranda, PhD, is studying an additional behavior shared by some viruses: the ability to remain dormant in a cell for years, not actively replicating or causing harm, but avoiding detection and thereby hindering a complete recovery. While most commonly associated with HIV, other viruses like Epstein-Barr—a type of herpes virus that infects the immune system and can lead to several different cancers—also display this behavior.

Dr. Miranda is working on ways to restart these dormant viruses, with the ultimate goal of killing them. “The idea that you need to reactivate a latent virus is something that we herpes researchers have been thinking about for decades,” says Dr. Miranda. “In the last five years or so, HIV scientists, like my colleagues here at Gladstone, have been trying to do the same thing, and the early research into herpes has really helped to inform that, including repurposing the same drugs for HIV that first worked in herpes.”

However, Dr. Miranda says that he and others are now concerned that in deliberately reactivating one virus, several others may be revived in the process, which could have unintended health consequences. Because of this, his focus has started to shift towards being more selective. Dr. Miranda is currently researching how to restart just the Epstein-Barr virus in cancerous tumors so that the activated cells serve as a beacon for chemotherapy drugs, enabling them to target the cancerous cells without the risk of setting off other dormant viruses.

Meanwhile, other Gladstone researchers are searching for drugs to exclusively reactivate HIV using different drug compounds. Dr. Miranda says that these parallel efforts are important to be able to compare drugs across viruses in order to find the best matches. “Working at a place like Gladstone is great because we have people researching both herpes and HIV, so we can take this work that is being done in tandem and come up with a common, systematic framework that applies to various diseases.”