Researchers have uncovered the first evidence that a virus can mutate to evade the body's first line of immune defense. The discovery may help explain why people with AIDS or others with compromised immunity may suffer severe infections from viruses that they would otherwise defeat.
In studies published in the June 2004 issue of the journal Immunity, the researchers found that the mouse version of cytomegalovirus (MCMV) is capable of mutating to evade natural killer (NK) cells. NK cells are major weapons of the innate immune system, the component of the immune system that attacks infections first. This more generalized component of the immune system quickly springs into action to knock down infections. In the process, it buys precious time for the immune system's more specific second line of defense, known as acquired immunity, which must adapt and proliferate to target a particular invading virus or microorganism.
Howard Hughes Medical Institute investigator Wayne M. Yokoyama at Washington University School of Medicine in St. Louis led the research group. Yokoyama and his colleagues collaborated with researchers from the Max von Pettenkoffer-Institute in Germany and the University of Rijeka in Croatia.
Although it has long been known that viruses such as HIV can mutate to evade the immune system, those mutations permit the virus to circumvent acquired immunity, said Yokoyama. Previous studies suggested that only RNA viruses underwent mutation and escaped, rather than the DNA viruses, whose replication is believed to be less prone to rapid mutation.
In earlier studies with mice, Yokoyama and his colleagues had shown how MCMV triggers NK cells to attack and kill cells infected with the virus. They demonstrated that the virus makes a protein called m157. The presence of this viral protein on the surface of an infected cell allows NK cells to recognize and destroy it.
In the experiments described in the Immunity article, the researchers exposed mice lacking an acquired immune system — but with normal NK cells — to MCMV. They discovered that although the mice survived initially, they died within several weeks of infection.
“That was a surprising finding, and it raised many questions about what the virus was doing during this period,” said Yokoyama. “Our subsequent analysis revealed that the viruses that grew out at three to four weeks after infection were not the same genetically as the ones that we put in.” The researchers found that the MCMV virus that eventually overcame the innate immunity of the mice had developed mutations in the gene for m157 that rendered the virus essentially “invisible” to NK cells.
One question, however, was whether the mutant m157 pre-existed in a small percentage of the viruses in the initial infection or whether the virus produced new mutations as it replicated, said Yokoyama. To show that the virus could, indeed, produce new mutations, the researchers infected mice with a viral culture that they knew contained no mutant m157. They found that there were different m157 mutations in each mouse, suggesting that mutations were independently developing in each infected mouse, allowing the viruses to escape detection by NK cells.