HIV Research Today is a free monthly online journal that collates and summarizes the latest research about HIV, including details on human immunodeficiency virus, testing, treatment, prevention, vaccines, aids. | ||||||||
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CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis.Herbeuval JP, Grivel JC, Boasso A, Hardy AW, Chougnet C, Dolan MJ, Yagita H, Lifson JD, Shearer GM Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. gene_shearer@nih.gov 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. Published 3 November 2005 in Blood, 106(10): 3524-31.
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