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.