LONDON - A new study of cytomegalovirus (CMV) provides fresh insight into the ways that viruses manipulate host cells to avoid the attention of the immune system. A team of scientists in the UK has shown that CMV has a mechanism for switching off natural killer (NK) cells, suggesting that these cells have a key role to play in controlling CMV infection.

"This discovery turns the spotlight on NK cells. What we know about their activity is already very interesting, and their role in viral infections needs to be explored further," Andrew McMichael, director of the Medical Research Council's Human Immunology Unit at the Institute of Molecular Medicine at the University of Oxford in the UK, told BioWorld International.

McMichael and his colleagues in Oxford, in a collaboration with Gavin Wilkinson and colleagues in the Department of Medicine at University of Wales College of Medicine in Cardiff, report their findings in a paper in the Feb. 11, 2000, Science titled, "Surface Expression of HLA-E, an Inhibitor of Natural Killer Cells, Enhanced by Human Cytomegalovirus gpUL40."

The immune system normally deals with viral infections as follows:

Cells infected with viruses display fragments of viral proteins on their surfaces associated with molecules belonging to the major histocompatibility complex (MHC), of the group known as class I. (In humans, the MHC is known as the human leukocyte antigen, or HLA.)

Cytotoxic T lymphocytes (CTLs), which encounter viral peptides presented by MHC molecules, will kill the infected cells. Many viruses, however, have evolved ways of downregulating the class I MHC molecules that are required for this type of immune response. To counter this strategy, the immune system relies on NK cells, which kill cells nonspecifically, selecting them simply on the basis that they have no class I MHC molecules on their surface and that a virus must therefore be lurking inside.

McMichael's group has a long-standing interest in the interactions between viruses and the immune system, including the ways in which the immune system controls viruses, and how viruses have evolved to escape these strategies. Part of its work has involved studying a molecule called HLA-E, which is a member of the nonclassical MHC class I molecules.

Veronique Braud, of the Institute of Molecular Medicine, showed two years ago, with a study published in Nature, that HLA-E binds to NK cells and can inhibit their function.

McMichael explained: "Our findings were quite remarkable. We found that, inside cells, HLA-E binds predominantly to one peptide, which comes from the leader sequence of other class I HLA molecules. If that peptide is not present, HLA-E stays inside the cell. So HLA-E is, if you like, a marker for the presence of the classical HLA molecules - HLA-A, HLA-B and HLA-C."

These studies also showed that, once on the surface of the cell, HLA-E binds to the NK cell receptor CD94/NKG2A, and, as a consequence, inhibits the function of these cells.

McMichael added, "In other words, when classical HLA class I molecules are present, HLA-E is also present and NK cells are inhibited. When HLA class I molecules are absent, HLA-E is not expressed and NK cells kill the cell."

Following this work, Braud, who, along with Peter Tomasec of University of Wales is joint first author of the Science paper, scanned genetic sequence databases to see what else had the same sequence.

She discovered, McMichael said, the "perfect match" in a protein of CMV called UL40. The team went on to show that UL40 can stimulate cells to produce more copies of HLA-E, so presumably protecting them from attack by NK cells.

One of the ways in which CMV brings about downregulation of class I HLA molecules is by blocking TAP, a transporter protein that is associated with antigen processing. If TAP were blocked, it normally would also prevent HLA-E from reaching the surface, too. But McMichael and his colleagues were interested to see that the mechanism by which UL40 upregulates HLA-E is independent of TAP. He said, "We show that this happens in cells that do not have TAP, and in the presence of the CMV gene that inhibits TAP."

Next, the group plans to examine the mechanism by which upregulation of HLA-E happens in CMV-infected cells, and in different cell types. Some studies will involve CMV mutants that lack UL40.

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