Human immunodeficiency virus-specific circulating CD8 T lymphocytes have down-modulated CD3zeta and CD28, key signaling molecules for T-cell activation

J Virol. 2000 Aug;74(16):7320-30. doi: 10.1128/jvi.74.16.7320-7330.2000.


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 CD3zeta, 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 CD3zeta down-modulation and possible CD8 T-cell functional defects, we used flow cytometry to characterize further the properties of the CD3zeta-down-modulated subset. HIV-specific CD8 T cells, identified by tetramer staining, are CD3zeta(-). CD8 T cells with down-modulated CD3zeta also do not express the key costimulatory receptor CD28 and have the cell surface phenotype of activated or memory T cells (HLA-DR(+) CD62L(-)). After T-cell activation, CD3zeta-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 CD3zeta is not reexpressed even after IL-2 exposure.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CD28 Antigens / metabolism*
  • CD3 Complex / metabolism*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytokines / metabolism
  • Down-Regulation
  • Flow Cytometry
  • HIV Infections / immunology
  • HIV-1 / immunology*
  • Humans
  • Immunologic Memory
  • Interleukin-2 / metabolism
  • Lymphocyte Activation
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Interleukin-2 / metabolism


  • CD28 Antigens
  • CD3 Complex
  • CD3 antigen, zeta chain
  • Cytokines
  • Interleukin-2
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-2