Development of a Broad-Spectrum Antiviral Agent

One of our lab's research projects involves investigating vaccine resistance to viruses and resistance to autoimmune diseases. This project grew out of concern about the global health threat posed by viruses.

Of primary concern is that pharmaceuticals aren't available for the majority of naturally emerging or bioterrorism-engineered viruses. The limited success of vaccines and inhibitory drugs as antiviral therapeutics necessitates more novel approaches. Modulation of cellular antiviral defense mechanisms provides an approach to exploit endogenous signaling cascades for therapeutic benefit.

Our lab discovered that transgenic expression of the Theiler's Murine encephalomyelitis virus (TMEV) gene, 3D polymerase, in FVB mice results in a mouse that is resistant to virus infections.

These FVB-3D mice are able to withstand lethal challenges with encephalomyocarditis virus (ECMV), which causes fatal heart disease in humans. In addition, the mice survived infection with herpes viruses, which can cause a variety of disabling diseases in humans, including fatal encephalitis. Further, the mice survived infection with vesicular stomatitis virus, which is typically transmitted by insects and causes ulcers in the mouths of animals. Infecting them with the different groups of viruses proved that the mice can withstand infections with both RNA and DNA viruses.

Resistance to this lethal virus challenge is the result of transgenic expression of 3D initiating expression of prominent antiviral response genes in all organ groups. Another remarkable feature of the FVB-3D mice is that despite constitutive expression of type I interferon responsive genes, these animals are devoid of autoimmunity.

These mice breed perfectly well in the laboratory and live a normal life span without diseases. They're phenotypically normal, except for being highly resistant to virus infection

Significance to patient care

Understanding how these mice fight off infection might provide insight into how to generate a vaccine that could function against all viruses in the world. Research shows that the gene that was inserted in these mice created the response. That suggests it's possible that our lab could generate a similar strategy in humans either before or after potentially lethal virus infections. Another potential outcome is better understanding of why these mice don't develop autoimmune disease.

The dogma in science is that up-regulation of these antiviral genes, such as the natural interferons, causes many autoimmune diseases in experimental animals and possibly in humans. Because these mice don't develop autoimmunity, it provides a unique opportunity to understand why this doesn't occur.