Dr. David Koelle and his colleagues at the UW are looking for needles in a viral haystack.
“Herpes is a very big virus, with a genome of more than 160,000 base pairs,” says Koelle, associate professor of medicine in the Division of Allergy and Infectious Diseases. “That’s more than 10 times more complicated than the cold virus or HIV, in terms of numbers of amino acids encoded by the genome.”
Some people have severe recurrent herpes simplex virus (HSV), while others have very infrequent symptoms or are asymptomatic. HSV-1 is associated with cold sores; HSV-2 is associated with genital herpes. Researchers hypothesize that there is something different in the immune response to HSV-2 between persons with frequent symptoms and persons with asymptomatic infection. When a person infected with HSV-2 experiences an “outbreak,” viral shedding may or may not be accompanied by a skin lesion.
Little is known about how the body’s immune system recognizes the HSV virus. During a herpes outbreak, the immune system mounts a T-lymphocyte immune response when it detects a small number of proteins encoded by the HSV genome.
“To better understand this immune response, we need to know the identity of these short stretches of proteins produced by the virus and recognized by the immune system during a herpes outbreak,” says Koelle. “These protein chains are only eight to10 amino acids long.”
Koelle and colleagues study a glycosylated skin-homing molecule called cutaneous lymphocyte-associated antigen (abbreviated CLA). This glycosylated molecule coats the outside of a select minority of circulating T-lymphocytes. CLA is able to bind to another molecule, called E-selectin, that is specifically expressed in the skin. Therefore, CLA marks T-lymphocytes equipped to “traffic” to skin. And HSV is a skin-infecting virus.
Using CLA as a specific marker, Koelle and his team purify skin-homing lymphocytes from blood samples. These purified cells are rich sources of HSV-specific lymphocytes. Using genetic libraries of HSV type 2 DNA, the eight to 10 amino acid pieces of HSV that are recognized by HSV-specific lymphocytes are then determined.
“We are building knowledge of the immune system’s response to the herpes virus,” says Koelle. “One day a vaccine may be developed using our research on skin-homing molecules.”
Koelle presents “Home Sweet Home: Glycosylated Skin-Homing Molecules and Other Strategies Used by the T-Cell Response to Genital Herpes” at the Science in Medicine lecture, at noon, Thursday, Feb. 20, in A-420 Hogness Auditorium, Health Sciences Center. Everyone is welcome.
Koelle received an M.D. degree in 1985 from the UW. He completed an internship and residency in internal medicine at Tufts-New England Medical Center in Boston. From 1989 to 1992 he was a postdoctoral fellow at the UW in infectious diseases. He joined the faculty as acting instructor of medicine in the Division of Allergy and Infectious Diseases in 1992.
Koelle is an attending physician at Harborview Medical Center, UW Medical Center and the Seattle Cancer Care Alliance. He is also an affiliate investigator at Virginia Mason Research Center in Seattle and the Fred Hutchinson Cancer Research Center. Koelle’s research is supported by the National Institutes of Health and is made possible by the collaborative efforts of a large team of investigators in Seattle.