Human immunodeficiency virus-specific circulating CD8 T lymphocytes have down-modulated CD3ζ and CD28, key signaling molecules for T-cell activation

Although human immunodeficiency virus (HIV)-infected subjects without AIDS have a high frequency of HIV-specific CD8 T lymphocytes, cellular immunity is unable to control infection. Freshly isolated lymphocytes often do not lyse HIV-infected targets in 4-h cytotoxicity assays. A large fraction of circulating CD8 T cells from HIV-infected donors down-modulate CD3 zeta, the signaling component of the T-cell receptor complex, which is reexpressed in vitro coincident with the return of cytotoxic function. To investigate further the link between CD3 zeta down-modulation and possible CD8 T-cell functional defects, we used flow cytometry to characterize further the properties of the CD3 zeta-down-modulated subset, HIV-specific CD8 T cells, identified by tetramer staining, are CD3 zeta(-). CD8 T cells with down-modulated CD3 zeta also do not express the key costimulatory receptor CD28 and have the cell surface phenotype of activated or memory T cells (BLA-DR+ CD62L(-)). After T-cell activation, CD3 zeta-down-modulated cells express the activation marker CD69 but not the high-affinity interleukin 2 (IL-2) receptor alpha-chain CD25 and produce gamma interferon but not IL-2. Therefore HIV-specific CD8 T cells have down-modulated key signaling molecules for T-cell activation and costimulation and require exogenous cytokine stimulation, The typical impairment of HIV-specific CD4 T helper cells, which would normally provide specific CD8 T-cell stimulation, means that in vivo CTL function in vivo is compromised in most HIV-infected individuals. In AIDS patients, the functional defect is more severe, since CD3 zeta is not reexpressed even after IL-2 exposure.