title: Limited sequence evolution within persistently targeted CD8 epitopes in chronic human immunodeficiency virus type 1 infection.
abstract: Studies in acute human immunodeficiency virus type 1 (HIV-1) infection indicate viral evolution under CD8 T-cell immune selection pressure, but the effects of ongoing immune pressure on epitope evolution during chronic infection are not well described. In this study, we performed a detailed longitudinal analysis of viral sequence variation within persistently targeted cytotoxic T-lymphocyte (CTL) epitopes in two HIV-1-infected persons during 6 years of persistent viremia. Responses were quantitated using freshly isolated peripheral blood lymphocytes in direct lytic assays as well as by gamma interferon (IFN-gamma) Elispot assays on cryopreserved cells. Seven targeted epitopes were identified in each person. In the majority of cases, the dominant epitope sequence did not change over time, even in the presence of responses of sufficient magnitude that they were detectable using fresh peripheral blood mononuclear cells in direct lytic assays. Only 4 of the 14 autologous epitopes tested represented potential CTL escape variants; however, in most cases strong responses to these epitopes persisted for the 6 years of study. Although persistent IFN-gamma responses were detected to all epitopes, direct lytic assays demonstrated declining responses to some epitopes despite the persistence of the targeted sequence in vivo. These data indicate limited viral evolution within persistently targeted CD8 T-cell epitopes during the chronic phase of infection and suggest that these regions of the virus are either refractory to sequence change or that persistently activated CD8 T-cell responses in chronic infection exert little functional selection pressure.
authors.affiliation: Partners AIDS Research Center, Massachusetts General Hospital, and Division of AIDS, Harvard Medical School, Boston, USA.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Koibuchi
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.forename: Stanley K
authors.initials: SK
authors.lastname: Mui
authors.forename: Kristin M
authors.initials: KM
authors.lastname: O'Sullivan
authors.forename: Alicja
authors.initials: A
authors.lastname: Trocha
authors.forename: Spyros A
authors.initials: SA
authors.lastname: Kalams
authors.forename: R Paul
authors.initials: RP
authors.lastname: Johnson
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D000595:Amino Acid Sequence; D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D017931:DNA Primers; D000939:Epitopes / Q000032:analysis / Q000235:genetics; D019143:Evolution, Molecular; D014644:Genetic Variation; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D016133:Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019562:Viral Load
chemical_list: D017931:DNA Primers; D000939:Epitopes