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We tested CD4 T-cell reactivity against each viral protein in persons immunized with vaccinia virus (VV), either recently or more than 40 years ago, as a model self-limited viral infection. Similar tests were done with persons with herpes simplex virus 1 (HSV-1) infection as a model chronic infection. We used an indirect method capable of counting the CD4 T cells in blood reactive with each individual viral protein. Each person had a clear CD4 T-cell dominance hierarchy. The top four open reading frames accounted for about 40% of CD4 virus-specific T cells. Early and long-term memory CD4 T-cell responses to vaccinia virus were mathematically indistinguishable for antigen breadth and immunodominance. Despite the chronic intermittent presence of HSV-1 antigen, the CD4 T-cell dominance and diversity patterns for HSV-1 were identical to those observed for vaccinia virus. The immunodominant CD4 T-cell antigens included both long proteins abundantly present in virions and shorter, nonstructural proteins. Limited epitope level and direct<jats:italic>ex vivo<\/jats:italic>data were also consistent with pronounced CD4 T-cell immunodominance. We conclude that human memory CD4 T-cell responses show a pattern of pronounced immunodominance for both chronic and self-limited viral infections and that this pattern can persist over several decades in the absence of antigen.<\/jats:p>","DOI":"10.1128\/jvi.03047-12","type":"journal-article","created":{"date-parts":[[2012,12,20]],"date-time":"2012-12-20T10:12:43Z","timestamp":1355998363000},"page":"2617-2627","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":30,"title":["CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence"],"prefix":"10.1128","volume":"87","author":[{"given":"Lichen","family":"Jing","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua T.","family":"Schiffer","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Washington, Seattle, Washington, USA"},{"name":"Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiana M.","family":"Chong","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph J.","family":"Bruckner","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. 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