Scientists can't prove it yet, but they suspect the missing immune system component, a group of molecules known as the Major Histocompatibility Complex (MHC) Class Ia, has a previously unrecognized backup that is similar enough to step in and fill the void left by its absence. If so, that backup may become a new focus for efforts to design antiviral vaccines.
"This surprising finding contradicts a long-held belief about control of viral infection: that the immune system must have MHC Class I molecules to recognize and destroy virus-infected cells," says senior author Skip Virgin, M.D., Ph.D., professor of pathology and immunology and of molecular microbiology. "It also suggests that we may need to take a more extensive look at what immune system elements play a role in controlling chronic viral infections."
The study will be published in the May issue of Public Library of Science Pathogens.
In chronic herpes virus infections, the body brings the invader under control, reducing its replication and spread, but is unable to completely eliminate it, resulting in lifelong infection.
The mice in the study were injected with murine gamma herpes virus 68, a herpes virus that infects mice and is closely related to the human gamma herpes viruses Epstein-Barr virus (EBV, the cause of mononucleosis) and Kaposi's sarcoma-associated herpes virus (KSHV, the cause of a form of cancer known as Kaposi's sarcoma). Other herpes viruses that infect humans include the alpha herpes viruses herpes simplex virus 1 and 2, which cause cold sores and genital herpes, and varicella zoster virus, which causes chickenpox. Infection with gamma herpes viruses such as EBV and KSHV increases the risk of some cancers, especially in persons with weakened immune systems.
Immune system cells known as CD8 or cytotoxic T cells are responsible for recognizing virus-infected cells and killing them or sounding alarms that summon other defensive measures. To enable this recognition process, other cells regularly chop up viral proteins found in their interiors and display them on their surfaces. MHC Class I molecules act as a kind of stage for this inspection process, binding to the protein parts as they are sent to the surface and allowing CD8 T cells to recognize the presence of a foreign invader. When the CD8 T cells recognize a viral protein part, they either destroy the cell displaying the part or emit inflammatory hormones known as cytokines that trigger other immune defense measures.
Because the genetically modified mice used in their experiment lacked the genes that contain instructions for making MHC Class I molecules, Virgin and his colleagues expected to see little response from CD8 T cells when they injected the mice with herpes virus. Initially, that was exactly what they found.
"This was a study of chronic infection, though, and when we looked at the mice seven weeks later, we were surprised to find the mice making a very robust and effective CD8 T cell response," he says. "This suggests there's an alternate way of generating CD8 T cells."
The researchers believe a closely related stand-in for MHC Class I makes it possible for mouse CD8 T cells to recognize and fight the virus.
"It would be reasonable for there to be backup plans, particularly given that some viruses have evasion strategies that they use to block the classical antigen recognition processes that rely on MHC Class I," Virgin says.
Follow-up studies now underway have produced preliminary evidence that these backup plans may be active even when normal MHC Class I is engaged in the fight against chronic infection. Additional studies will look at whether the backup system can enable an active immune response to other chronic infectious agents.
Some current efforts to develop antiviral vaccines focus exclusively on portions of viral proteins likely to be picked up and presented by MHC Class I molecules. If these backup mechanisms are important to control of herpes and other chronic diseases, they may pick up and display other parts of viral proteins for CD8 T cells to recognize. If so, vaccine developers may need to revise their approach in order to create vaccines that trigger the most potent antiviral immune responses.
"The ultimate relevance of these backup systems to human disease isn't known yet, but it's worth noting that we never would have even known to look for them if it weren't for our ability to study genetically altered mice," he says.
By Michael Purdy
Braaten DC, McClellan JS, Messaoudi I, Tibbetts SA, McClellan KB, Nikoli-Zugich J, Virgin HW IV. Effective control of chronic gamma-herpesvirus infection by unconventional MHC Class Ia-independent CD8 T cells. Public Library of Science Pathogens, May 2006. Funding from the National Institutes of Health, the Leukemia and Lymphoma Society and the Cancer Research Institute supported this research.
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