Now, researchers currently at Cedars-Sinai Medical Center, and the Universidad Autonoma de Madrid, in Spain, report that treating a common virus with a mutation-causing cancer drug caused the virus to mutate so much that it was no longer able to reproduce and was driven to extinction. The findings, reported in the current issue of the Proceedings of the National Sciences (PNAS), and preceded by a Commentary by Nobel-Prize winning Professor Manfred Eigen from the Max Planck Institut fur biophysikalische Chemie, Goettingen, Germany, may ultimately lead to new ways to treat and eliminate viral infections.
"We found that a specific chemical mutagen caused the virus to mutate so much that the replication process was ultimately aborted," said Pedro Lowenstein, M.D., Ph.D., Director of the Board of Governor's Gene Therapeutics Research Institute at Cedars-Sinai Medical Center. "These findings, may lead, in the future, to ways to stop viruses from reproducing in humans in the same way."
"Although the possibility to exploit high mutation rates in viruses was already known, this and other work is providing the basis for more rapid progress in this field," said collaborator and co-author Esteban Domingo, Ph.D, Director of the Laboratory of Genetic Variability of RNA Viruses at the Center for Molecular Biology 'Severo Ochoa', Universidad Autonoma de Madrid, Spain.
Viruses are genetic entities that can cause a number of infections and diseases in humans such as the common cold, chickenpox, shingles, herpes, polio, influenza and AIDS. Infections occur when a virus comes into contact with a host cell and injects its genetic material, literally taking over the cell's function. Subsequently, the infected cell produces more viral protein and genetic material instead of its usual products.
But for viruses to reproduce and spread, they must make many copies of their genetic material. In RNA viruses, such as those discussed here, this process occurs when a viral enzyme reads the sequence of the viruses' genome within the host cell and transcribes it into a complementary RNA or DNA sequence. Yet, the process is error-prone, as mistakes occur during replication when the genome sequence is read and transcribed, resulting in mutations in the viral genome.
Capitalizing on the viruses' tendency to make errors during the replicating process, the investigators tested two types of mutation-inducing cancer drugs in cells infected with lymphocytic choriomeningitis virus (LCMV), a virus that can infect both mice and humans. To do this, the investigators infected hamster cells, grown in culture, with the virus and treated them with either 5-fluorouracil (FU) or 5-azacytidine (AZC). The viruses' ability to replicate and the amount of mutations that occurred in the viral genomes was then measured and compared at varying doses of either FU or AZC. The researchers found that both FU and AZC increased the number of mutations in all areas of the viruses' genetic machinery even at lower doses. However, only higher doses of FU were able to drive the virus to extinction, while treatment with AZC at any dose level was not effective to eliminate the virus.
"Given that FU eliminated this particular virus, while AZC did not suggests that different mutagens will be more effective than others in the treatment of viruses," commented Dr. Lowenstein. "This work also lays the groundwork for future studies to determine how mutagens actually slow down the replication process and, at the same time, may lead to new treatments that succeed where others have limited effectiveness."
Although viral extinction was likely due to an increase in the mutation rate caused by FU, the investigators were unable to track the viruses' mutations as they progressed closer to extinction.
"This was likely due to the fact that highly mutated genomes are either undetectable with current methods, or that the mutations obtained and detected were already sufficient to block further viral replication," said Dr. Lowenstein.
"That the introduction of more mutations could help combat viral disease seemed totally unrealistic a decade ago. Now, despite obvious difficulties and a lot of work to be done, it is a sound scientific proposition," commented Dr. Domingo.
Cedars-Sinai Medical Center is one of the largest nonprofit academic medical centers in the Western United States. For the fifth straight two-year period, Cedars-Sinai has been named Southern California's gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthrough in biomedical research and superlative medical education. Named one of the 100 "Most Wired" hospitals in health care in 2001, the Medical Center ranks among the top 10 non-university hospitals in the nation for its research activities.
Journal
Proceedings of the National Academy of Sciences