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

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.