High viral burden in the presence of major HIV‐specific CD8+ T cell expansions: evidence for impaired CTL effector function

• Published in: European journal of immunology 2001-03, Vol.31 (3), p.677-686
• Main Authors: Kostense, Stefan, Ogg, Graham S., Manting, Erik H., Gillespie, Geraldine, Joling, Jeanine, Vandenberghe, Kristin, Veenhof, Eveline Z., Baarle, Debbie van, Jurriaans, Suzanne, Klein, Michèl R., Miedema, Frank
• Format: Article
• Language: English
• Subjects: CD4 Lymphocyte Count; Cells, Cultured; CTL; Disease Progression; Epitopes - genetics; Epitopes - immunology; Gene Products, nef - immunology; HIV Antigens - genetics; HIV Antigens - immunology; HIV Core Protein p24 - genetics; HIV Core Protein p24 - immunology; HIV Infections - immunology; HIV Infections - virology; HIV/AIDS; HLA Antigens - immunology; Humans; IFN‐γ; Interferon-gamma - biosynthesis; Lymphocyte Activation; MHC‐peptide complex; Mutation; nef Gene Products, Human Immunodeficiency Virus; Phenotype; T-Lymphocytes, Cytotoxic - immunology; Viral Load
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/1521-4141(200103)31:3<677::AID-IMMU677>3.0.CO;2-M

To investigate the effect of HIV‐specific CD8+ T cells on viral plasma load and disease progression, we enumerated HLA‐A2‐, B8‐ and B57‐restricted CD8+ T cells directed against several HIV epitopes in a total of 54 patients by the use of tetrameric HLA‐peptide complexes. In patients with high CD4+ T cell numbers, HIV‐specific tetramer+ cells inversely correlated with viral load. Patients with CD4+ T cell numbers below 400/μ l blood, however, carried high viral load despite frequently having high tetramer+ T cell numbers. This lack of correlation between viral load and tetramer+ cells did not result from viral escape variants, as in only 4 of 13 patients, low frequencies of viruses with mutated epitopes were observed. In 15 patients we measured CD8+ T cell antigen responsiveness to HIV peptide stimulation in vitro. FACS analyses showed differential IFN‐γ production of the tetramer+ cells, and this proportion of IFN‐γ‐producing tetramer+ cells correlated with AIDS‐free survival and with T cell maturation to the CD27– effector stage. These data show that most HIV‐infected patients have sustained HIV‐specific T cell expansions but many of these cells seem not to be functional, leaving the patient with high numbers of non‐functional virus‐specific CD8+ T cells in the face of high viral burden.