HIV-mediated phosphatidylinositol 3-kinase/serine-threonine kinase activation in APCs leads to programmed death-1 ligand upregulation and suppression of HIV-specific CD8 T cells

Karuppiah Muthumani, Devon J. Shedlock, Daniel K. Choo, Paolo Fagone, Omkar U. Kawalekar, Jonathan Goodman, Chaoran B. Bian, Aarti A. Ramanathan, Parikh Atman, Pablo Tebas, Michael A. Chattergoon, Andrew Y. Choo, David B. Weiner

Research output: Contribution to journalArticlepeer-review

Abstract

Recent evidence demonstrates that HIV-1 infection leads to the attenuation of cellular immune responses, which has been correlated with the increased expression of programmed death (PD)-1 on virus-specific CD8+ T cells. PD-1 is induced upon T cell activation, and its prolonged expression facilitates CD8+ T cell inhibitory signals when bound to its B7 family ligands, PD-ligand (L)1/2, which are expressed on APCs. Importantly, early reports demonstrated that blockade of the PD-1/PD-L interaction by Abs may help to counter the development of immune exhaustion driven by HIV viral persistence. To better understand the regulation of the PD-1 pathway during HIV infection, we examined the ability of the virus to induce PD-L expression on macrophages and dendritic cells. We found a direct relationship between the infection of APCs and the expression of PD-L1 in which virus-mediated upregulation induced a state of nonresponsiveness in uninfected HIV-specific T cells. Furthermore, this exhaustion phenotype was revitalized by the blockade of PD-L1, after which T cells regained their capacity for proliferation and the secretion of proinflammatory cytokines IFN-γ, IL-2, and IL-12 upon restimulation. In addition, we identify a critical role for the PI3K/serine-threonine kinase signaling pathway in PD-L1 upregulation of APCs by HIV, because inhibition of these intracellular signal transducer enzymes significantly reduced PD-L1 induction by infection. These data identify a novel mechanism by which HIV exploits the immunosuppressive PD-1 pathway and suggest a new role for virus-infected cells in the local corruption of immune responses required for viral suppression.

Original languageEnglish (US)
Pages (from-to)2932-2943
Number of pages12
JournalJournal of Immunology
Volume187
Issue number6
DOIs
StatePublished - Sep 15 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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