"These findings not only provide a better understanding of viral infections," says study leader Ted H. Hansen, Ph.D., professor of genetics, "they also offer novel insights into basic cellular processes in the immune system."
Like police cars cruising a neighborhood, immune cells known as cytotoxic T cells patrol the body looking for signs of trouble, such as virus-infected cells.
Cells communicate with the immune system by displaying protein fragments on their surface, including viral proteins. When cytotoxic T cells find viral proteins on a cell's surface, they destroy the cell and thereby eliminate the virus.
Molecules known as major histocompatibility complex class 1 (MHC class 1) are responsible for displaying the protein fragments, known as peptides, on the cell surface. Cells make fleets of MHC class 1 molecules, each of which is assembled from two separate pieces plus the peptide. After each MHC class 1 molecule is completed, it travels to the cell surface to display its peptide to passing immune cells.
"MHC class I is the body's most important mechanism for fighting off most viral infections," says lead author Lonnie P. Lybarger, Ph.D., postdoctoral fellow in genetics. "Not surprisingly, herpes viruses have evolved ways to block that immune response."
Hansen, Lybarger and their colleagues used a mouse virus known as gamma2-herpesvirus to discover exactly how the virus does this. The virus is closely related to the human herpes virus associated with Kaposi's sarcoma, a cancer of blood vessels that occurs in some people with AIDS.
Research has shown that cells assemble MHC class 1 molecules with the help of other molecules known as chaperones. In this study, the investigators found that in cells infected with gamma2-herpesvirus, a viral protein known as mK3 joins the chaperones as they prepare to assemble an MHC class 1 molecule.
Then, as assembly occurs, the mK3 protein makes a subtle change in the MHC class 1 molecule that marks it as waste. So instead of traveling to the cell surface as it should, the MHC class 1 molecule is shunted off to the side and destroyed.
"The finding that mK3 requires chaperone molecules to function and hides out with them came as a surprise," says Lybarger. "It represents a new strategy for blocking immune detection, and it suggests that there are probably other viral proteins that use host molecules to target MHC class 1."
The researchers are using gamma2-herpesvirus and the herpes virus associated with Kaposi's sarcoma to identify some of those additional protein-protein interactions between virus and host.
Hansen attributes the success of this project to an effective collaboration between his laboratory, which specializes in the presentation of MHC class 1 molecules, and the virology laboratory of Herbert W. Virgin IV, M.D., Ph.D., professor of pathology and immunology and of molecular microbiology.
Lybarger L, Wang X, Harris MR, Virgin HW, Hansen TH. Virus subversion of the MHC class 1 peptide-loading complex. Immunity, January 2003.
Funding from the National Institute of Allergy and Infectious Diseases supported this research.
Journal
Immunity