Granule-dependent mechanisms of lysis are defective in CD8 T cells of HIV-infected, antiretroviral therapy-treated individuals

Daria Trabattoni, Stefania Piconi, Mara Biasin, Giuliano Rizzardini, Marco Migliorino, Elena Seminari, Adriano Boasso, Luca Piacentini, Maria Luisa Villa, Renato Maserati, Mario Clerici

Research output: Contribution to journalArticle

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-α, 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-γ-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-α 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-γ 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.

Original languageEnglish
Pages (from-to)859-869
Number of pages11
JournalAIDS (London, England)
Volume18
Issue number6
DOIs
Publication statusPublished - Apr 9 2004

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Keywords

  • AIDS/HIV
  • Antiretroviral therapy
  • CD8 T cells
  • Cytokines
  • Cytotoxicity
  • Perforin

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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