Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

Abstract

Human immunodeficiency virus (HIV) accessory protein viral protein R (Vpr) plays a key role in virus replication and induces cell cycle arrest and apoptosis in various cell types including T cells and neuronal and tumor cells following infection withApoptosis is an active process mediated by programmed signaling pathways that can be initiated by a variety of intracellular and extracellular stimuli. Apoptosis is essential to many biological processes including functional self-organizational processes in the immune and central nervous systems, morphogenetic changes in embryonic development, tissue homeostasis, and normal cell turnover (1). It also plays a critical role in the pathogenesis of a variety of diseases including cancer and infectious diseases (1, 2). Modulation of apoptosis may be closely associated with the outcome of a disease process. For example, resistance to apoptosis is one of the important mechanisms by which cancer cells evade destruction by the immune system (1). Therefore, effective therapies against such diseases should ideally induce efficient cytotoxicity to override apoptotic resistance. Recently the viral protein R (Vpr) 3 of the human immunodeficiency virus (HIV) has been proposed as a novel antiproliferative agent in vivo because of its ability to induce apoptosis in normal and tumor cell lines, including leukemialymphoma, colon, and cervical carcinoma cell lines (3, 4), and its ability to transduce cells effectively without carriers or receptor targeting strategies (5, 6).Vpr, a 14-kDa 96-amino acid protein, is the most conserved and multifunctional regulatory protein. It plays a key role in virus replication by causing nuclear translocation of the HIV-1 preintegration complex and transcriptional regulation of the HIV long terminal repeat (7-10). It has also been shown to induce cell cycle arrest at the G 2 /M phase and apoptosis in a variety of cell types including T cells, neutrophils, and neuronal cells following infection with Vpr-expressing HIV isolates or exposure to the extracellular Vpr protein (7,11). Recently Vpr was detected in the sera and cerebrospinal fluid of HIV-infected subjects at levels similar to those of p24 antigen (5, 12). Moreover circulating Vpr was found to be biologically active in inducing virion production from latently infected cells, inducing apoptosis and causing depletion of bystander cells in lymphoid tissues during HIV infection (5,12).Multiple functions of Vpr have been attributed to its different domains (13). The Vpr protein is characterized by three well defined ␣-helices: 17-33, 40 -48, and 55-83 surrounded by flexible negatively charged N-terminal and basic C-terminal * This work was supported in part by grants from the Canadian Institutes of Health Research (to A. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 (14). Furthermore the amphipathic ␣-helix 55-83...

HIV-1 Nef Inhibits Lipopolysaccharide-induced IL-12p40 Expression by Inhibiting JNK-activated NFκB in Human Monocytic Cells

“…Isolation of Monocytes-Monocytes were purified from PBMCs by negative selection as described earlier (16,35). Briefly, PBMCs were incubated with magnetic polystyrene Dynabeads (Dynal Biotech, Oslo, Norway) coated with anti-CD2 (T cells) and anti-CD19 (B cells) antibodies for 30 min on ice for depletion of T and B cells, respectively.…”

Anti-apoptotic mechanisms of HIV: lessons and novel approaches to curing HIV

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HIV-1 Vpr—a still “enigmatic multitasker”

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