Responsiveness of HIV-specific CD4 T cells to PD-1 blockade

Blood. 2011 Jul 28;118(4):965-74. doi: 10.1182/blood-2010-12-328070. Epub 2011 Jun 7.


Defining the T helper functions impaired by programmed death-1 (PD-1) is crucial for understanding its role in defective HIV control and determining the therapeutic potential of targeting this inhibitory pathway. We describe here the relationships among disease stage, levels of PD-1 expression, and reversibility of CD4 T-cell impairment. PD-L1 blockade in vitro enhanced HIV-specific production of Th0 (IL-2), Th1 (IFN-γ), Th2 (IL-13), and TFH (IL-21) cytokines by CD4 T cells. PD-L1 blockade caused an early increase in cytokine transcription and translation that preceded cell proliferation. Although the impact of PD-L1 blockade on cytokine expression and, to a lesser extent, cell proliferation was associated with markers of disease progression, restoration of cytokine secretion was also observed in most subjects with undetectable viremia. PD-L1 blockade restored cytokine secretion in both PD-1intermediate and PD-1high sorted CD4 T-cell subsets. Compared with PD-1high HIV-specific CD8 T cells, PD-1high HIV-specific CD4 T cells showed lower expression of the inhibitory molecules CD160 and 2B4, demonstrating marked differences in expression of inhibitory receptors between T-cell subsets. These data show that PD-1 impairs HIV-specific T helper responses both by limiting expansion of these cells and by inhibiting effector functions of multiple differentiated CD4 T-cell subsets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism
  • Apoptosis Regulatory Proteins / antagonists & inhibitors*
  • B7-H1 Antigen
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Separation
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Flow Cytometry
  • HIV Infections / immunology*
  • HIV Infections / metabolism
  • Humans
  • Immunophenotyping
  • Programmed Cell Death 1 Receptor
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism


  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • B7-H1 Antigen
  • CD274 protein, human
  • Cytokines
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor