Regulation of TNF-related apoptosis-inducing ligand on primary CD4 + T cells by HIV-1: Role of type I IFN-producing plasmacytoid dendritic cells

Jean Philippe Herbeuval, Andrew W. Hardy, Adriano Boasso, Stephanie A. Anderson, Matthew J. Dolan, Michel Dy, Gene M. Shearer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

139 Scopus citations

Abstract

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, was suggested to contribute to HIV-1 pathogenesis by inducing CD4+ T cell death characteristic of AIDS. We previously reported HIV-1-mediated, TRAIL-induced apoptosis in primary CD4+ T cells in vitro and observed elevated levels of plasma TRAIL in HIV-1-infected patients. The present study elucidates the unresolved mechanism by which HIV-1 induces TRAIL expression on primary CD4+ T cells. We demonstrate that the expression of TRAIL by primary CD4+ T cells is regulated by IFN-α that is produced by HIV-1-stimulated plasmacytoid dendritic cells (pDCs). We also found that IFN-induced TRAIL is mediated by signal transducers and activators of transcription 1 and 2. We show that IFN-α production by HIV-1-activated pDCs is blocked by an early viral entry inhibitor of CD4-gp120 binding, but not by inhibitors of viral coreceptor binding. Our in vitro data are supported by the demonstration that anti-IFN-α and -β Abs inhibit apoptosis and TRAIL expression in CD4+ T cells from HIV-1-infected patients. Our findings suggest a potential unique role of pDCs in the immunopathogenesis of HIV-1 infection by inducing the death molecule TRAIL.

Original languageEnglish
Pages (from-to)13974-13979
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number39
DOIs
StatePublished - 27 Sep 2005
Externally publishedYes

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