CD4+ T-cell death induced by infectious and noninfectious HIV-1: Role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis

Jean Philippe Herbeuval, Jean-Charles B. Grivel, Adriano Boasso, Andrew W. Hardy, Claire Chougnet, Matthew J. Dolan, Hideo Yagita, Jeffrey D. Lifson, Gene M. Shearer

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Abstract

It has been proposed that direct and indirect mechanisms contribute to the unresolved issue of CD4+ T-cell depletion that results from HIV-1 infection. We recently reported that plasma levels of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) are elevated in HIV-1-infected patients and that they correlate with viral load. The present study investigates the expression of TRAIL death receptor 5 (DR5) in the peripheralblood mononuclear cells (PBMCs) of HIV-1-infected patients and its role in CD4 + T-cell death. DR5 expression was elevated and associated with the apoptotic marker annexin V. Apoptosis was reduced in CD4+ T cells when cultured with anti-DR5 antibody. CD4+, but not CD8+, T cells from uninfected donors expressed TRAIL, DR5, and activated caspase-3 when cultured with infectious or noninfectious HIV-1, resulting in preferential apoptosis of CD4+ T cells. TRAIL, caspase-3 expression, and apoptosis were type 1 interferon (IFN) dependent. Induction of apoptosis and DR5 expression required glycoprotein 120 (gp120)-CD4 interaction. Finally, we analyzed DR5 expression by CD4+ T cells in highly active antiretroviral therapy (HAART)-treated patients. The decreased viral loads and increased CD4 counts of HAART-responsive patients were associated with a decrease in DR5 mRNA expression by CD4+ T lymphocytes. We propose a novel model in which a type 1 IFN-regulated TRAIL/DR5 mechanism induces apoptosis of HIV-1-exposed CD4+ T cells.

Original languageEnglish
Pages (from-to)3524-3531
Number of pages8
JournalBlood
Volume106
Issue number10
DOIs
Publication statusPublished - 15 Nov 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Herbeuval, J. P., Grivel, J-C. B., Boasso, A., Hardy, A. W., Chougnet, C., Dolan, M. J., Yagita, H., Lifson, J. D., & Shearer, G. M. (2005). CD4+ T-cell death induced by infectious and noninfectious HIV-1: Role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis. Blood, 106(10), 3524-3531. https://doi.org/10.1182/blood-2005-03-1243