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

Tory Johnson, Karan Patel, Kory R. Johnson, Dragan Maric, Peter Calabresi, Rodrigo Hasbun, Avindra Nath

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)13588-13593
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number33
DOIs
Publication statusPublished - Aug 13 2013

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Keywords

  • Central nervous system
  • Chromatin
  • Chronic inflammation
  • CNS inflammation
  • Lymphocyte

ASJC Scopus subject areas

  • General

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