title: Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic.
abstract: Despite the frequency of HIV-specific CD8 T cells, most HIV-infected patients do not control viral replication without antiviral drugs. Although CD8 T cells are important in containing acute HIV and simian immunodeficiency virus (SIV) infection, CD8 T-cell functions are compromised in chronic infection. To investigate whether functional deficits are specific to HIV, the phenotypic and functional properties of HIV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV)-specific CD8 T cells, labeled with HLA A2.1 or B8 tetramers, were compared in 35 HIV-infected and 9 healthy donors. Cytotoxic T lymphocytes express the cytolytic molecules perforin and granzymes, and are thought to be CD45RA(+)CD27(-). Although most HIV- specific cells are antigen experienced and express granzyme A (median, 85%), few express high levels of perforin (median, 10%) or CD45RA (median, 14%) or have down-modulated CD27 (median, 12%). Perforin expression by HIV-specific cells is not significantly different from that of EBV- or CMV-specific cells in the same donors or in healthy donors. EBV- and CMV-specific cells, like HIV-specific cells, are often not cytotoxic when tested directly ex vivo. HIV-specific T-cell expression of other phenotypic markers is similar to that of EBV- and CMV-specific CD8 T cells in healthy donors. However, CMV-specific cells (and, to a lesser extent, EBV-specific cells) in HIV-infected donors are more likely to be CD27(-), CD45RA(+), and GzmA(+). These results suggest that the chance to eradicate an infection by T-cell-mediated lysis may be undermined once an infection becomes chronic. Impaired antiviral cytotoxicity during chronic infection is not specific to HIV but likely represents the immune response to chronic antigenic exposure.
authors.affiliation: Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.forename: Premlata
authors.initials: P
authors.lastname: Shankar
authors.forename: Zhan
authors.initials: Z
authors.lastname: Xu
authors.forename: Brooke
authors.initials: B
authors.lastname: Harnisch
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Hernan
authors.initials: H
authors.lastname: Valdez
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D002908:Chronic Disease; D003587:Cytomegalovirus / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006678:HIV / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016130:Immunophenotyping; D008562:Membrane Glycoproteins / Q000032:analysis*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis; D014777:Virus Diseases / Q000276:immunology
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D054353:Perforin