Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein

Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13588-93. doi: 10.1073/pnas.1308673110. Epub 2013 Jul 29.


Chronic immune activation is a major complication of antiretroviral therapy (ART) for HIV infection and can cause a devastating immune reconstitution inflammatory syndrome (IRIS) in the brain. The mechanism of T-cell activation in this population is not well understood. We found HIV-Tat protein and IL-17-expressing mononuclear cells in the brain of an individual with IRIS. Tat was also present in the CSF of individuals virologically controlled on ART. Hence we examined if Tat protein could directly activate T cells. Tat transcriptionally dysregulated 94 genes and induced secretion of 11 cytokines particularly activation of IL-17 signaling pathways supporting the development of a proinflammatory state. Tat increased IL-17 transcription and secretion in T cells. Tat entered the T cells rapidly by clathrin-mediated endocytosis and localized to both the cytoplasm and the nucleus. Tat activated T cells through a nonclassical pathway dependent upon vascular endothelial growth factor receptor-2 and downstream secondary signaling pathways but independent of the T-cell receptor. However, Tat stimulation of T cells did not induce T-cell proliferation but increased viral infectivity. This study demonstrates Tat's role as a virulence factor, by driving T-cell activation and contributing to IRIS pathophysiology. This supports the necessity of an anti-Tat therapy in conjunction with ART and identifies multiple targetable pathways to prevent Tat-mediated T-cell activation.

Keywords: CNS inflammation; central nervous system; chromatin; chronic inflammation; lymphocyte.

Publication types

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

MeSH terms

  • Anti-Retroviral Agents / adverse effects*
  • Anti-Retroviral Agents / therapeutic use
  • Brain / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression Regulation, Viral / immunology*
  • HIV Infections / drug therapy*
  • Humans
  • Immune Reconstitution Inflammatory Syndrome / etiology
  • Immune Reconstitution Inflammatory Syndrome / immunology
  • Immune Reconstitution Inflammatory Syndrome / physiopathology*
  • Immunoblotting
  • Interleukin-17 / metabolism
  • Leukocytes, Mononuclear / metabolism
  • Lymphocyte Activation / immunology
  • Microarray Analysis
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology
  • Virulence Factors / cerebrospinal fluid
  • Virulence Factors / metabolism*
  • tat Gene Products, Human Immunodeficiency Virus / cerebrospinal fluid
  • tat Gene Products, Human Immunodeficiency Virus / metabolism*


  • Anti-Retroviral Agents
  • Interleukin-17
  • Virulence Factors
  • tat Gene Products, Human Immunodeficiency Virus

Associated data

  • GEO/GSE44460