Our understanding of how CD4(+) T cells can regulate CD8(+) T cell responses in HIV infection is still incomplete. Recent evidence obtained in mice suggests that CD4(+) T cell help is required for efficient CD8(+) T cell-mediated immunity in chronic infection: CD8(+) T cells primed in the absence of such help release the TNF-related apoptosis-inducing ligand TRAIL and undergo apoptosis. Using a novel ELISPOT assay, in the present study we show that CD8(+) T cells are also a source of the antigen-specific TRAIL response in HIV-infected patients with CD4(+) T cell counts below 200. In patients with CD4(+) T cell counts above 200 TRAIL was not detectable. Accordingly, antigens to which patients have likely been exposed when CD4(+) T cell levels were high (e.g., influenza, CMV, and EBV) did not induce TRAIL. Within the HIV-positive donor population with low CD4(+) T cell counts a dissociation of the interferon-gamma (IFN-gamma) and TRAIL response to different HIV peptide epitopes was detectable suggesting impaired immunity to antigens that triggered TRAIL in the absence of IFN-gamma. Our findings emphasize that "helpless" CD8(+) T cells, i.e., cells that have been primed in the absence of CD4(+) T cell help, may play a crucial role in HIV infection. A "helpless" phenotype may impair CD8(+) T cell control of HIV and other infections and possibly contribute to the depletion of CD4(+) T cells via apoptosis. Immunizations and infections in this "helpless" state might result in ineffective CD8(+) T cell responses.