Activation associated ERK1/2 signaling impairments in CD8+ T cells co-localize with blunted polyclonal and HIV-1 specific effector functions in early untreated HIV-1 infection

PLoS One. 2013 Oct 15;8(10):e77412. doi: 10.1371/journal.pone.0077412. eCollection 2013.


We recently observed that a large proportion of activated (CD38(+)HLA-DR(+)) CD8(+) T cells from recently HIV-1-infected adults are refractory to phosphorylation of ERK1/2 kinases (p-ERK1/2-refractory). Given that the ERK1/2 pathway mediates intracellular signaling critical for multiple T cell functions, including key effector functions, the loss of ERK1/2 responsiveness may have broad consequences for CD8(+) T cell function. In the current study, we hypothesized that the p-ERK1/2-refractory population, localized largely within the activated CD38(+)HLA-DR(+) CD8(+) T cell population, would display impairments in CD8(+) T cell effector functions, such as cytokine production and degranulation, compared to CD8(+) p-ERK1/2-responsive cells. We further hypothesized that the p-ERK1/2-refractory phenotype is persistent over time during untreated infection, and would correlate with poorer virologic control, in a manner independent of CD8(+) T cell activation level. We performed single-cell resolution, flow cytometric assays of phospho-kinase responses paired to intracellular cytokine staining in one assay to examine IFN-γ, perforin and CD107α responses in CD8(+) T cells by ERK1/2 signaling profile. On a per cell basis, p-ERK1/2-refractory cells, which fall predominantly within the activated CD8(+) T cell compartment, produced less IFN-γ in response to polyclonal or HIV-1 antigen-specific stimulation, and expressed lower levels of perforin and CD107α. The p-ERK1/2 refractory cell population displayed minimal overlap with the PD-1 and Tim-3 inhibitory exhaustion markers and predicted high viral load independent of activation, suggesting that ERK1/2 may be a unique marker and point of intervention for improving CD8(+) T cell function. Blunted effector functions, secondary to ERK1/2 signaling deficits concentrated within activated CD8(+) T cells, may contribute to immunodeficiency and underlie the predictive capacity of CD8(+) T cell activation on HIV-1 disease progression. (270/300).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity / drug effects
  • Adult
  • Anti-HIV Agents / pharmacology
  • Anti-HIV Agents / therapeutic use
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • HIV Infections / drug therapy
  • HIV Infections / immunology*
  • HIV Infections / metabolism
  • HIV-1 / drug effects
  • HIV-1 / immunology
  • HIV-1 / physiology*
  • Humans
  • Interferon-gamma / biosynthesis
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phenotype
  • Phosphoproteins / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / immunology*
  • Species Specificity
  • Time Factors
  • Viral Load / drug effects
  • gag Gene Products, Human Immunodeficiency Virus / pharmacology


  • Anti-HIV Agents
  • Phosphoproteins
  • gag Gene Products, Human Immunodeficiency Virus
  • Interferon-gamma
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3