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Departments of
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Medicine,
Laboratory Medicine,
Immunology, and
Epidemiology, University of Washington, Seattle, WA 98195;
¶ Fred Hutchinson Cancer Research Center, Clinical Division, Seattle, WA 98109; and
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Virginia Mason Research Center, Seattle, WA 98101
HSV-2 causes chronic infections. CD8 CTL may play several
protective roles, and stimulation of a CD8 response is a rational
element of vaccine design for this pathogen. The viral Ags recognized
by CD8 T cells are largely unknown. It has been hypothesized that HSV
inhibition of TAP may favor recognition of virion input proteins or
viral immediate early proteins. We tested this prediction using
HSV-specific CD8 CTL clones obtained from genital HSV-2 lesions. Drug
and replication block experiments were consistent with specificity for
the above-named classes of viral proteins. Fine specificity was
determined by expression cloning using molecular libraries of viral
DNA, and peptide epitopes recognized at nanomolar concentrations were
identified. Three of four clones recognized the viral tegument proteins
encoded by genes UL47 and UL49. These
proteins are transferred into the cytoplasm on virus entry. Processing
of the tegument Ag-derived epitopes was TAP dependent. The
tegument-specific CTL were able to lyse HLA class I-appropriate
fibroblasts after short times of infection. Lysis of keratinocytes
required longer infection and pretreatment with IFN-
. Another clone
recognized an immediate early protein, ICP0. Lymphocytes specific for
these lesion-defined epitopes could be reactivated from the PBMC of
additional subjects. These data are consistent with an influence of HSV
immune evasion genes upon the selection of proteins recognized by CD8
CTL in lesions. Tegument proteins, identified for the first time as Ags
recognized by HSV-specific CD8 CTL, are rational candidate vaccine
compounds.
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