Anti-human immunodeficiency virus type 1 (HIV-1) CD8(+) T-lymphocyte reactivity during combination antiretroviral therapy in HIV-1-infected patients with advanced immunodeficiency

The long-term efficacy of combination antiretroviral therapy may relate to augmentation of anti-human immunodeficiency virus type 1 (HIV 1) CD8(+) T-c ell responses. We found that prolonged treatment of late-stage HIV-1-infect ed patients with a protease inhibitor and two nucleoside reverse transcript ase inhibitors failed to restore sustained, high levels of HIV-1-specific, HLA class I-restricted, cytotoxic-T-lymphocyte precursors and gamma interfe ron (IFN-gamma) production by CD8+ T cells. In some patients, particularly those initiating three drug combination therapy simultaneously rather than sequentially, there were early, transient increases in the frequency of ant i-HIV-1 CD8(+) T cells that correlated with decreases in HIV-1 RNA and incr eases in T-cell counts. In the other patients, HIV-1-specific T-cell functi ons either failed to increase or declined from baseline during triple-drug therapy, even though some of these patients showed suppression of plasma HI V-1 RNA. These effects of combination therapy were not unique to HIV-1 spec ific T-cell responses, since similar effects were noted for CD8(+) T cells specific for the cytomegalovirus pp65 matrix protein, The level and breadth of CD8+ cell reactivity to HLA A*02 HIV-1 epitopes, as determined by IFN-g amma production and HLA tetramer staining after combination therapy, were r elated to the corresponding responses prior to treatment. There was, howeve r, a stable, residual population of potentially immunocompetent HIV-1-speci fic T cells remaining after therapy, as shown by tetramer staining of CD8() CD45RO(+) cells, These results indicate that new strategies will be neede d to target residual, immunocompetent HIV-1-specific CD8(+) T cells to enha nce the effectiveness of antiretroviral therapy in patients with advanced i mmunodeficiency.