MIT biologists and colleagues have discovered the mechanism used by one virus to evade the body's immunological radar. An understanding of such mechanisms could help researchers combat viral infections.
The body protects itself against viruses by mounting an immune response against virally infected cells and killing them. This is possible because the soldiers in this war, antiviral T cells, are able to recognize infected cells. They do so via receptors that bind to fragments (peptides) of virus proteins attached to cell surface molecules.
The cell surface molecules in question, MHC class I proteins, are synthesized inside the cell then transported to the cell surface. During this journey they bind to peptides generated inside the cell. If the cell is infected by a virus, the MHC proteins also pick up viral peptides, which are similarly transported to the surface. The infected cell is thus marked as infected and is killed by the T cells. It follows that, if a virus could evolve a means to block this peptide presentation mechanism, infected cells would escape recognition and survive to produce more virus.
Last year researchers in the laboratory of Professor Hidde L. Ploegh of the Center for Cancer Research (CCR) and the Department of Biology described one way in which this can happen. Herpes simplex virus synthesizes a protein which blocks the delivery of viral peptides to the MHC proteins.
Now Emmanuel J.H.J. Wiertz, a postdoctoral fellow in the Ploegh lab, and colleagues report in a recent issue of Cell on the mechanism used by the human cytomegalovirus (HCMV) to escape detection. Other MIT authors of the paper are Professor Ploegh and Matthew Bogyo, a graduate student in biology at the CCR. Authors from other institutions are Thomas R. Jones and Lei Sun of Wyeth-Ayerst Research, and Hans J. Geuze of the Utrecht University School of Medicine in the Netherlands.
The researchers found that HCMV, which can cause significant disease, especially in immunologically compromised people, directly blocks production of the MHC protein itself. It does so by producing a single gene product called US11 that causes rapid degradation and breakdown of MHC soon after its initial synthesis inside the cell. Although the precise mechanism by which US11 subverts the proper processing of MHC is not yet known, it has the effect of preventing presentation of viral peptide antigens on the cell surface. In this way, the virus evades the surveillance of the immune system, sneaks in under the body's defenses and multiplies to cause disease.
This is another elegant example of the co-evolution of host and pathogen; the host evolves complex mechanisms to protect itself and the pathogen evolves clever tricks to evade them.
The work was supported by the National Institutes of Health. Dr. Wiertz was further supported by a Talent Stipendium of The Netherlands Organization for Scientific Research and a Long Term Fellowship from the European Molecular Biology Organization.
(This article is adapted from a longer piece that appeared in the March 1996 issue of the MIT Center for Cancer Research Newsletter.)