The hallmark of chronic viral infections is a progressive exhaustion of antigen-specific CD8+ T cells that leads to persisting viral replication. It is generally believed that exhaustion is a consequence of the accumulation of multiple inhibitory receptors on CD8+ T cells that makes them dysfunctional. Here, we show that during human chronic HIV-1 infection, a CD8+ T-cell positive costimulatory pathway mediated by DNAX-activating molecule-1 is also disrupted. Thus, DNAX-activating molecule-1 downregulation on CD8+ T cells aggravates the impairment of CTL effector function in chronic HIV-1 infection. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.