Focal glomerulosclerosis in proviral and c-fms transgenic mice links Vpr expression to HIV-associated nephropathy

Dickie, Peter; Roberts, Amanda; Uwiera, Richard R. E.; Witmer, Jennifer; Sharma, Kirti Rani; Kopp, Jeffrey B.

doi:10.1016/j.virol.2004.01.026

Cited by 56 publications

(41 citation statements)

References 58 publications

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“…Brain Tissues Prepared from Vpr-transgenic Mice-Vpr transgenic mice were described previously, in which vpr was under the control of the c-fms (M-CSF receptor) promoter, permitting expression mainly in monocytoid cells (7,29).…”

Section: Cytosolic Camentioning

confidence: 99%

Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders

Mukerjee

Chang

Valle

et al. 2011

Journal of Biological Chemistry

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Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction.The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and vsynaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders.Although effective in prolonging the life expectancy in patients with HIV infection (1), the highly active antiretroviral therapy (HAART) 2 in fact has resulted in an increased prevalence of HIV-associated neurocognitive disorders (HAND) (2). The molecular mechanisms leading to this phenomenon remain to be elucidated. Several reports indicated that HIVinfected macrophages and microglia produce neurotoxins (e.g. viral and cellular proteins) that have the ability to cause neuronal deregulation and to promote HAND (3, 4). The viral protein R (Vpr) is among the released HIV-1 proteins that have been considered to be deleterious to neurons; however the molecular mechanisms involved remain unclear (5-7). Vpr is packaged into the virion, and is essential for HIV-1 replication in macrophages (8, 9). Infected brain cells have been shown to release Vpr that could affects neuronal growth (10). Vpr mediates multiple functions, including nuclear import of the HIV-1 pre-integration complex, G 2 cell cycle arrest, transactivation of both viral replication, and host genes and induction of apoptosis (11,12). Vpr was also detected in a soluble form in CSF and sera of HIV-infected patients displaying neurological disorders (10). Vpr causes neuronal degeneration both in vitro and in vivo (7,10,13).A calcium channel is an ion channel, which displays selective permeability to Ca 2ϩ ions. It is sometimes synonymous as voltage-dependent Ca 2ϩ channel (VDCC) (14). Activation of particular VDCCs allows Ca 2ϩ entry into the cell, which depending on the cell type, results in muscular contraction, excitation of neurons, up-regulation of gene expression, or release of neuro...

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Section: Cytosolic Camentioning

confidence: 99%

Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders

Mukerjee

Chang

Valle

et al. 2011

Journal of Biological Chemistry

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“…Vpr transgenic mice were generated as described previously (Dickie et al, 2004) in which vpr was under the control of the c-fms (M-CSF receptor) promoter, permitting expression chiefly in monocytoid cells. Four-month-old Vpr transgenic and littermate wild-type mice were subjected to three behavioral tests: the inverted screen test at 20 and 40 cm and the horizontal bar test as described previously (Guenther et al, 2001).…”

Section: Methodsmentioning

confidence: 99%

HIV-1 Vpr Causes Neuronal Apoptosis andIn VivoNeurodegeneration

Jones¹,

Barsby²,

Cohen³

et al. 2007

J. Neurosci.

125

180

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“…Recent studies have demonstrated a central role for HIV-1 Vpr in HIVAN pathogenesis (12,14,15,40) and that Vpr induces apoptosis and hyperploidy in RTEC (28). However, the mechanisms by which Vpr induces RTEC apoptosis are unknown.…”

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confidence: 99%

FAT10: a Novel Mediator of Vpr-Induced Apoptosis in Human Immunodeficiency Virus-Associated Nephropathy

Snyder

Alsauskas

Gong

et al. 2009

J Virol

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Human immunodeficiency virus (HIV)-associated nephropathy is a significant cause of morbidity and mortality in HIV-infected persons. Vpr-induced cell cycle dysregulation and apoptosis of renal tubular epithelial cells are important components of the pathogenesis of HIV-associated nephropathy (HIVAN). FAT10 is a ubiquitin-like protein that is upregulated in renal tubular epithelial cells in HIVAN. In these studies, we report that Vpr induces increased expression of FAT10 in tubular cells and that inhibition of FAT10 expression prevents Vpr-induced apoptosis in human and murine tubular cells. Moreover, we found that Vpr interacts with FAT10 and that these proteins colocalize at mitochondria. These studies establish FAT10 as a novel mediator of Vpr-induced cell death.

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Focal glomerulosclerosis in proviral and c-fms transgenic mice links Vpr expression to HIV-associated nephropathy

Cited by 56 publications

References 58 publications

Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders

Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders

HIV-1 Vpr Causes Neuronal Apoptosis andIn VivoNeurodegeneration

FAT10: a Novel Mediator of Vpr-Induced Apoptosis in Human Immunodeficiency Virus-Associated Nephropathy

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