A C-terminal domain of HIV-1 accessory protein Vpr is involved in penetration, mitochondrial dysfunction and apoptosis of human CD4+ lymphocytes

Arunagiri, Chinniah K.; Macreadie, Ian; Hewish, Dean R.; Azad, Ahmed A.

doi:10.1023/a:1026487609215

Cited by 59 publications

(62 citation statements)

References 55 publications

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“…Vpr was shown to cause cell cycle arrest and apoptosis in T cells (9,27). To determine whether monocytic cells exposed to Vpr peptides undergo apoptosis, THP-1 cells were treated with Vpr-(52-96) or Vpr-(1-45) peptides for 24 h followed by measurement of apoptosis.…”

Section: Vpr-(52-96) Peptide Induces Apoptosis Through the Mitochondrmentioning

confidence: 99%

“…The amino acid sequence of these peptides is as follows: Vpr-(52-96), DTWAGVEAIIRILQQ-LLFIHFRIGCRHSR IGVTRQRRARNGASRS; Vpr-(1-45), MEQAPEDQGPQREPYNEWTLELLEELKSEAVRHFPRIW-LHNLGQH. Because of the high propensity of Vpr peptides to bind to proteins, cells (1 ϫ 10 6 /ml) were treated with peptides in an isotonic buffer (13 mM HEPES, 2.4% glucose, 68 mM NaCl, 1.3 mM KCL, 4 mM Na 2 HPO 4 , 0.7 mM KH 2 PO 4 , pH 7.2) for 30 min followed by addition of culture medium as described previously (27).…”

Section: Isolation Of Monocytes From Peripheral Blood Mononuclearmentioning

confidence: 99%

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

Mishra

Kumar

2007

Journal of Biological Chemistry

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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...

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Section: Vpr-(52-96) Peptide Induces Apoptosis Through the Mitochondrmentioning

confidence: 99%

Section: Isolation Of Monocytes From Peripheral Blood Mononuclearmentioning

confidence: 99%

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

Mishra

Kumar

2007

Journal of Biological Chemistry

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“…All of the peptides tested contained a motif, designated H (F/S) RIG, which has been previously identified as mediating the penetration of Vpr into CD4 + lymphocytes with concomitant induction of mitochondrial dysfunction and apoptosis. 61 Although all of the peptides contained this motif, not all of these peptides mediated equivalent inhibition of B16.F10 proliferation. In fact, as indicated above, the more carboxy of these peptides, within the 65-91 amino acid region, inhibited proliferation progressively less than the more amino fragments.…”

Section: Discussionmentioning

confidence: 98%

Anti-tumor activity mediated by protein and peptide transduction of HIV viral protein R (Vpr)

Muthumani

Lambert²,

Shanmugam³

et al. 2009

Cancer Biology & Therapy

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“…Mapping studies performed on isolated mitochondria revealed that the N-terminal 1-51 aa of Vpr, Vpr , are vital for virion incorporation and nuclear localization, whereas the Cterminal 52-96 aa, Vpr , induce cell-cycle arrest and apoptosis (11,17,19,20). Vpr can cause apoptosis either upon infection with Vpr-expressing HIV isolates or following exposure of cells to the purified protein (14,15,21). We and others have shown that this apoptotic effect is mimicked by Vpr but not by the Vpr(1-51) moiety (13,22).…”

mentioning

confidence: 99%

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

Saxena

Busca

Pandey

et al. 2011

The Journal of Immunology

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Monocytic cells survive HIV replication and consequent cytopathic effects because of their decreased sensitivity to HIV-induced apoptosis. However, the mechanism underlying this resistance to apoptosis remains poorly understood. Lymphocytic cells are exposed to microbial products because of their translocation from the gut in persons with chronic HIV infections or following coinfections. We hypothesized that activation of monocytic cells by such microbial products through interaction with corresponding TLRs may confer antiapoptotic signals. Using HIV-viral protein R (Vpr)(52–96) peptide as a model apoptosis-inducing agent, we demonstrated that unlike monocyte-derived macrophages, undifferentiated primary human monocytes and promonocytic THP-1 cells are highly susceptible to Vpr(52–96)-induced apoptosis. Interestingly, monocytes and THP-1 cells stimulated with TLR9 agonist CpG induced almost complete resistance to Vpr(52–96)-induced apoptosis, albeit through a TLR9-independent signaling pathway. Moreover, CpG selectively induced the antiapoptotic cellular inhibitor of apoptosis (c-IAP)-2 protein and inhibition of the c-IAP-2 gene by either specific small interfering RNA or synthetic second mitochondrial activator of caspases mimetic reversed CpG-induced resistance against Vpr(52–96)-mediated apoptosis. We demonstrated that c-IAP-2 is regulated by the JNK and calcium signaling pathway, in particular calmodulin-dependent protein kinase-II. Furthermore, inhibition of JNK and the calcium signaling including the calmodulin-dependent protein kinase-II by either pharmacological inhibitors or their specific small interfering RNAs reversed CpG-induced protection against Vpr(52–96)-mediated apoptosis. We also show that CpG induced JNK phosphorylation through activation of the calcium signaling pathway. Taken together, our results suggest that CpG-induced protection may be mediated by c-IAP-2 through the calcium-activated JNK pathway via what appeared to be TLR9-independent signaling pathways.

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A C-terminal domain of HIV-1 accessory protein Vpr is involved in penetration, mitochondrial dysfunction and apoptosis of human CD4+ lymphocytes

Cited by 59 publications

References 55 publications

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

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

Anti-tumor activity mediated by protein and peptide transduction of HIV viral protein R (Vpr)

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

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