Single-cell, phosphoepitope-specific analysis demonstrates cell type- and pathway-specific dysregulation of Jak/STAT and MAPK signaling associated with in vivo human immunodeficiency virus type 1 infection

J Virol. 2008 Apr;82(7):3702-12. doi: 10.1128/JVI.01582-07. Epub 2008 Jan 23.

Abstract

Despite extensive evidence of cell signaling alterations induced by human immunodeficiency virus type 1 (HIV-1) in vitro, the relevance of these changes to the clinical and/or immunologic status of HIV-1-infected individuals is often unclear. As such, mapping the details of cell type-specific degradation of immune function as a consequence of changes to signaling network responses has not been readily accessible. We used a flow cytometric-based assay of signaling to determine Janus kinase/signal transducers and activators of transcription (Jak/STAT) signaling changes at the single-cell level within distinct cell subsets from the primary immune cells of HIV-1-infected donors. We identified a specific defect in granulocyte-macrophage colony-stimulating factor (GM-CSF)-driven Stat5 phosphorylation in the monocytes of HIV-1+ donors. This inhibition was statistically significant in a cohort of treated and untreated individuals. Ex vivo Stat5 phosphorylation levels varied among HIV-1+ donors but did not correlate with CD4(+) T-cell counts or HIV-1 plasma viral load. Low Stat5 activation occurred in HIV-1-infected donors despite normal GM-CSF receptor levels. Investigation of mitogen-activated protein kinase (MAPK) pathways, also stimulated by GM-CSF, led to the observation that lipopolysaccharide-stimulated extracellular signal-regulated kinase phosphorylation is enhanced in monocytes. Thus, we have identified a specific, imbalanced monocyte signaling profile, with inhibition of STAT and enhancement of MAPK signaling, associated with HIV-1 infection. This understanding of altered monocyte signaling responses that contribute to defective antigen presentation during HIV-1 infection could lead to immunotherapeutic approaches that compensate for the deficiency.

Publication types

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

MeSH terms

  • Adolescent
  • Antigens, Surface / analysis
  • CD4 Lymphocyte Count
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Extracellular Signal-Regulated MAP Kinases*
  • Female
  • Flow Cytometry
  • HIV Infections / immunology*
  • HIV Infections / metabolism
  • HIV-1 / immunology*
  • Humans
  • Infant
  • Male
  • Monocytes / chemistry
  • Phosphorylation
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / analysis
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction*
  • Viral Load

Substances

  • Antigens, Surface
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • STAT5 Transcription Factor
  • Extracellular Signal-Regulated MAP Kinases