CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis.
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 peripheral-blood 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.
Herbeuval
Jean-Philippe
JP
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. gene_shearer@nih.gov
Grivel
Jean-Charles
JC
Boasso
Adriano
A
Hardy
Andrew W
AW
Chougnet
Claire
C
Dolan
Matthew J
MJ
Yagita
Hideo
H
Lifson
Jeffrey D
JD
Shearer
Gene M
GM
D017304:Annexin A5 / Q000276:immunology; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000097:blood / Q000276:immunology*; D018791:CD4 Lymphocyte Count / Q000379:methods; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D053148:Caspase 3; D020169:Caspases / Q000276:immunology; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood / Q000276:immunology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D017304:Annexin A5; D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D015699:HIV Envelope Protein gp120; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases