Acute viral infections, including smallpox, may be halted by aiming a drug not at the virus but at the cellular machinery it needs to spread from cell to cell an approach that might eliminate the problem of antiviral drug resistance, report researchers supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The scientists say their finding, made using lab-grown monkey kidney cells and a mouse model of smallpox infection, turns the usual approach to fighting viral infections on its head. By developing drugs targeted to the unchanging chemical pathways used in normal cell processes and co-opted by viruses, the investigators say it might be possible to battle acute viral infections in a way that prevents the virus from mutating its way around a drug attack.
"The threat of smallpox virus being used as a bioterror weapon makes it imperative that we pursue not only improved vaccines to prevent the disease, but also novel therapeutic strategies such as this that could be employed quickly in the event of a deliberate release of the virus," says NIH Director Elias A. Zerhouni, MD.
Senior author Ellis L. Reinherz, MD, of the Dana-Farber Cancer Institute (DFCI), and colleagues at DFCI, the University of Massachusetts Medical School and the Centers for Disease Control and Prevention (CDC) published their study in the February issue of The Journal of Clinical Investigation. The portion of the research using smallpox virus was conducted at the CDC in highest level biosafety laboratories.
"This is noteworthy research. It shows that it is possible to block temporarily a cell signaling pathway and thereby inhibit activity of a virus," says NIAID Director Anthony S. Fauci, MD.
Current antiviral drugs target the virus itself. "In contrast, our approach short-circuits a cellular chemical pathway, making it unavailable to the virus and thus hindering the virus' ability to spread from cell to cell," says Reinherz. The kind of antiviral drug envisioned by Reinherz would not be used for lengthy periods because it would target normal and necessary cell functions. In acute infections, however, where short-term therapy could contain the infection until the host immune system is fully activated, such a drug could be very valuable, he says.
Virus-directed drugs tend to become less effective over time as the constantly mutating virus develops resistance to the drug, Reinherz explains. "The advantage of targeting signaling pathways is that cells and the structures that send and receive signals are far less likely to mutate than viruses themselves, making it improbable that drugs will lose their potency," he says.
The new findings build on earlier work by the researchers in which they determined that smallpox growth factor (SPGF), a protein produced by the smallpox virus, attaches to a cell membrane receptor called erb-B1. This interaction primes the cell to become a factory for producing new virus particles.
Could smallpox replication be hampered by specifically blocking the SPGF pathway? To find out, Reinherz and his team added an experimental drug, CI-1033, to monkey kidney cells that had been infected with smallpox virus. CI-1033, which is being developed by Pfizer Corporation as a potential cancer treatment, halts erb-B1's function. The investigators found that production of new virus particles and spread of the virus to uninfected cells was significantly impaired when erb-B1-blocking CI-1033 was present.
In other experiments, the researchers found that CI-1033, used preventively, offered significant protection from serious illness in mice infected with a relative of the smallpox virus. Mice receiving both CI-1033 and a single dose of an infection-fighting antibody completely cleared the virus from their lungs within eight days of the initial infection.
The researchers are searching for additional and complementary cell signaling pathways that might be temporarily blocked and either halt the spread of a virus from cell to cell or prevent infection altogether. Also, notes Reinherz, other viruses, including cytomegalovirus, exploit the erb-B pathway, suggesting that they too might be defeated through drugs that selectively block erb-B. While typically causing only mild disease, cytomegalovirus can be very serious in the young or in persons with compromised immune systems.
In a commentary accompanying the research article, Fauci and NIAID co-author Mark Challberg, PhD, write, "Inhibitors of the erb-B1 pathway as well as other cell-signal transduction pathways required for viral replication represent a largely untapped source of potential antiviral drugs and merit further exploration."
In addition to Reinherz, the other authors of the paper are Hailin Yang, PhD, Mikyung Kim PhD, and Pedro Reche, PhD, of DFCI; Sung-Kwon Kim, PhD, and Raymond Welsh, PhD, of the University of Massachusetts Medical School; and Tiara Morehead and Inger Damon, MD, PhD, of the CDC.
NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
Reference: H Yang et al. Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction. The Journal of Clinical Investigation 115:379-87 (2005).