TRAIL-Mediated Apoptosis in HIV-1-Infected Macrophages Is Dependent on the Inhibition of Akt-1 Phosphorylation

Abstract

HIV-1 uses mononuclear phagocytes (monocytes, tissue macrophages, and dendritic cells) as a vehicle for its own dissemination and as a reservoir for continuous viral replication. The mechanism by which the host immune system clears HIV-1-infected macrophages is not understood. TRAIL may play a role in this process. TRAIL is expressed on the cell membrane of peripheral immune cells and can be cleaved into a soluble, secreted form. The plasma level of TRAIL is increased in HIV-1-infected patients, particularly those with high viral loads. To study the effect of elevated TRAIL on mononuclear phagocytes, we used recombinant human (rh) TRAIL and human monocyte-derived macrophages (MDM) as an in vitro model. Our results demonstrated rhTRAIL-induced apoptosis in HIV-1-infected MDM and inhibited viral replication, while having a reduced effect on uninfected MDM. HIV-1 infection significantly decreased Akt-1 phosphorylation; rhTRAIL exposure further decreased Akt-1 phosphorylation. Infection with a dominant-negative Akt-1 adenovirus potentiated rhTRAIL-induced apoptosis, while constitutively active Akt-1 blocked rhTRAIL-induced apoptosis in HIV-1-infected MDM. From this data we conclude the death ligand TRAIL preferentially provokes apoptosis of HIV-1-infected MDM, and the mechanism is reliant upon the inhibition of Akt-1 phosphorylation. Understanding this mechanism may facilitate the elimination of HIV-1-infected macrophages and lead to new therapeutic avenues for treatment of HIV-1 infection.

Shift in Monocyte Apoptosis with Increasing Viral Load and Change in Apoptosis-Related ISG/Bcl2 Family Gene Expression in Chronically HIV-1-Infected Subjects

“…However, the well-established functional role of proapoptotic genes identified in this work as contributing to apoptosis lends support to the notion that their increased expression may impact apoptosis. Also, while we focused on the relationship between apoptosis and apoptosis-related gene families expressed within cells (p53, ISG, and Bcl2), our data do not exclude contributions by added external mechanisms in vivo affecting total monocyte numbers, such as de novo production and turnover described to occur in SIV infection (40,41) or external factors such as soluble TRAIL in viremic serum (35,38) or increased TRAILmediated apoptosis (30,34,37,75).…”

CpG Protects Human Monocytic Cells against HIV-Vpr–Induced Apoptosis by Cellular Inhibitor of Apoptosis-2 through the Calcium-Activated JNK Pathway in a TLR9-Independent Manner

“…However, we and others have shown that monocytic cells from HIV-infected patients and HIV-negative individuals when infected in vitro can undergo apoptosis (4,5). Moreover, MDMs were shown to undergo apoptosis following in vitro infection with HIV, which was mediated by downregulation of Akt-1 and the FOXO3a transcription factor (6,7). It appears that monocytic cells can undergo apoptosis but may escape HIV cytopathic effects as a result of certain factors reducing their sensitivity to apoptosis (8).…”

Induction of Plasma (TRAIL), TNFR-2, Fas Ligand, and Plasma Microparticles after Human Immunodeficiency Virus Type 1 (HIV-1) Transmission: Implications for HIV-1 Vaccine Design

“…This level of plasma TRAIL is well within the biologically relevant concentration range for induction of cell death in immune cells (34).…”

“…Unlike MPs, exosomes express endosomal markers. MPs have immunomodulatory activities and can promote immune cell death; exosomes are also immunologically active, can suppress immune responses (20,34,42,55), and have been reported to have been found at elevated levels in cases of chronic HIV-1 infection (4). If elevations in levels of immunosuppressive molecules, coupled with early CD4 ϩ T-cell death, occur early following HIV-1 transmission, then these events could potentially define a protected time during which HIV-1 is able to replicate while anti-HIV-1 T-or B-cell responses are suppressed.…”

“…MPs are small membrane-bound vesicles that are released from the surface of apoptotic cells by exocytic or budding processes; as such, MPs bear cell surface markers and can bind annexin V because of the expression of phosphatidylserine (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)39). MPs, which circulate in the blood under many clinical conditions, are part of a spectrum of subcellular structures that are released from cells and can be distinguished from exosomes, which are released from multivesicular bodies during activation.…”