title: Granule-dependent mechanisms of lysis are defective in CD8 T cells of HIV-infected, antiretroviral therapy-treated individuals.
abstract: BACKGROUND
  HIV-specific cytotoxic T-cell (CTL) responses are defective in HIV-infected patients undergoing antiretroviral therapy (ART). This defect has been attributed to the decreased antigenic burden secondary to ART-associated suppression of HIV-replication, and is responsible for the rebounds of viraemia that occur when patients interrupt therapy. CTL are stimulated by type 1 cytokines and can kill targets via granule-dependent (perforin and granzymes) and -independent (tumour necrosis factor-alpha, CD95) mechanisms.
  
  
  METHODS
  Granule-dependent and granule-independent mechanisms of CTL killing, as well as type 1 cytokine production by CD4 T cells, were analysed in 57 chronically HIV-infected ART-treated or ART-untreated individuals.
  
  
  RESULTS
  The results can be summarized as follows: the frequency of gp160 (env)-specific interferon-gamma-secreting CD8 T lymphocytes correlates positively with HIV viraemia in ART-treated and -untreated patients; Env-specific perforin- and granzymes-expressing CD8 T lymphocytes, and Env-stimulated perforin and granzymes mRNA, are reduced in ART-treated patients independently of HIV viral load and of type 1 cytokine production; tumour necrosis factor-alpha production is increased in ART-treated individuals; and Env-specific immature CD8+28+27+ cells are only marginally augmented in ART-treated patients, Similar results are observed in cytomegalovirus-specific CD8 T cells and peripheral blood mononuclear cells.
  
  
  CONCLUSIONS
  A defect of CTL function that selectively affects the granule-dependent mechanisms of lysis is observed in ART-treated individuals. Because interferon-gamma production is higher in these patients, this could be a defect primarily involving CTL. These data suggest an independence of CD8 T-cell numbers and their lytic ability in HIV-infected, ART-receiving patients. Immunomodulants are needed to successfully treat HIV infection.
authors.affiliation: Department of Immunology, University of Milan, Via GB Grassi 74, 20157 Milan, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Trabattoni
authors.forename: Stefania
authors.initials: S
authors.lastname: Piconi
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.forename: Giuliano
authors.initials: G
authors.lastname: Rizzardini
authors.forename: Marco
authors.initials: M
authors.lastname: Migliorino
authors.forename: Elena
authors.initials: E
authors.lastname: Seminari
authors.forename: Adriano
authors.initials: A
authors.lastname: Boasso
authors.forename: Luca
authors.initials: L
authors.lastname: Piacentini
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Villa
authors.forename: Renato
authors.initials: R
authors.lastname: Maserati
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000956:Antigens, Viral / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D018106:CD28 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002908:Chronic Disease; D003587:Cytomegalovirus / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D008875:Middle Aged; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018709:Statistics, Nonparametric; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014766:Viremia / Q000276:immunology; D019014:fas Receptor / Q000032:analysis
chemical_list: D019380:Anti-HIV Agents; D000956:Antigens, Viral; D015415:Biomarkers; D018106:CD28 Antigens; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma