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 lo ad and disease progression, we enumerated HLA-A2-, B8- and B57-restricted C D8(+) T cells directed against several HIV epitopes in a total of 54 patien ts by the use of tetrameric HLA-peptide complexes. In patients with high CD 4(+) T cell numbers, HIV-specific tetramer(+) cells inversely correlated wi th viral load. Patients with CD4(+) T cell numbers below 400/mul blood, how ever, carried high viral load despite frequently having high tetramer(+) T cell numbers. This lack of correlation between viral load and tetramer(+) c ells 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 pat ients we measured CD8(+) T cell antigen responsiveness to HIV peptide stimu lation in vitro. FAGS analyses showed differential IFN-gamma production of the tetramer(+) cells, and this proportion of IFN-gamma -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-functio nal virus-specific CD8(+) T cells in the face of high viral burden.