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

doi:10.1073/pnas.0505251102

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

^*Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; ^§Unité Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Faculté de Médecine René Descartes, 75270 Paris, France; and ^†Henry M. Jackson Foundation and ^‡Infectious Diseases Service, Wilford Hall Medical Center, Lackland Air Force Base, TX 78236-5300

Edited by Michael Sela, Weizmann Institute of Science, Rehovot, Israel (received for review June 22, 2005)

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.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: gene_shearer{at}nih.gov.
Author contributions: J.-P.H. and G.M.S. designed research; J.-P.H. and A.W.H. performed research; S.A.A., M.J.D., and M.D. contributed new reagents/analytical tools; J.-P.H., A.B., and M.D. analyzed data; and J.-P.H. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: TRAIL, TNF-related apoptosis-inducing ligand; mTRAIL, membrane TRAIL; pDC, plasmacytoid dendritic cell; DR, death receptor; STAT, signal transducers and activators of transcription; AT-2, Aldrithiol-2; SIV, simian immunodeficiency virus; sCD4, soluble CD4-IgG; PBMC, peripheral blood mononuclear cells; rIFN, recombinant IFN; AMD, AMD-3100; RANTES, regulated activation, normal T expressed and secreted.
↵ ∥ Feinberg, M. B., HIV Pathogenesis Keystone Symposia, April 9-15, 2005, Banff, Canada, abstr. no. 22.
Freely available online through the PNAS open access option.