Axonal Transport of Human Immunodeficiency Virus Type 1 Envelope Protein Glycoprotein 120 Is Found in Association with Neuronal Apoptosis

Bachis, Alessia; Aden, Sadia A.; Nosheny, Rachel L.; Andrews, Peter M.; Mocchetti, Italo

doi:10.1523/jneurosci.1054-06.2006

Cited by 83 publications

(141 citation statements)

References 62 publications

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“…Viral products such as HIV-1 gp120, Tat, and Vpr have been shown to be deleterious to neurons and to induce neuronal apoptosis (6,9,27,30,42). Recently, HIV-1-infected macrophages have been shown to affect neuronal development in a murine model (43), although the factors that affect neuronal development have not been identified and the mechanisms have not been clarified.…”

Section: Discussionmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Vpr Inhibits Axonal Outgrowth through Induction of Mitochondrial Dysfunction

Kitayama

Miura

Ando

et al. 2008

J Virol

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Human immunodeficiency virus type 1 (HIV-1)-infected macrophages damage mature neurons in the brain, although their effect on neuronal development has not been clarified. In this study, we show that HIV-1-infected macrophages produce factors that impair the development of neuronal precursor cells and that soluble viral protein R (Vpr) is one of the factors that has the ability to suppress axonal growth. Cell biological analysis revealed that extracellularly administered recombinant Vpr (rVpr) clearly accumulated in mitochondria where a Vpr-binding protein adenine nucleotide translocator localizes and also decreased the mitochondrial membrane potential, which led to ATP synthesis. The depletion of ATP synthesis reduced the transportation of mitochondria within neurites. This mitochondrial dysfunction inhibited axonal growth even when the frequency of apoptosis was not significant. We also found that point mutations of arginine (R) residues to alanine (A) residues at positions 73, 77, and 80 rendered rVpr incapable of causing mitochondrial membrane depolarization and axonal growth inhibition. Moreover, the Vpr-induced inhibition was suppressed after treatment with a ubiquinone analogue (ubiquinone-10). Our results suggest that soluble Vpr is a major viral factor that causes a disturbance in neuronal development through the induction of mitochondrial dysfunction. Since ubiquinone-10 protects the neuronal plasticity in vitro, it may be a therapeutic agent that can offer defense against HIV-1-associated neurological disease.

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Section: Discussionmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Vpr Inhibits Axonal Outgrowth through Induction of Mitochondrial Dysfunction

Kitayama

Miura

Ando

et al. 2008

J Virol

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“…Gp120 injected into the rat striatum or hippocampus is sequestered by neurons and subsequently retrogradely transported to distal neurons that project to these brain areas. Both retrograde transport of gp120 and apoptosis are dependent on CXCR4 (Bachis A et al, 2006).…”

Section: Neurotoxicity/neuroprotectionmentioning

confidence: 99%

“…Further, they found that TNF-α can induce neuronal apoptosis by directly binding to its receptor TNFR1 on the surface of neurons. Bachis A et al (2006) recently reported that cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL), hallmarks of apoptosis, were seen in neurons internalizing and transporting gp120. The retrograde transport of gp120 and apoptosis were mediated by the chemokine receptor CXCR4.…”

Section: Hiv-associated Encephalopathymentioning

confidence: 99%

Multiple roles of chemokine CXCL12 in the central nervous system: A migration from immunology to neurobiology

Ransohoff

2008

Progress in Neurobiology

307

245

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Chemotactic cytokines (chemokines) have been traditionally defined as small (10-14 kDa) secreted leukocyte chemoattractants. However, chemokines and their cognate receptors are constitutively expressed in the central nervous system (CNS) where immune activities are under stringent control. Why and how the CNS uses the chemokine system to carry out its complex physiological functions has intrigued neurobiologists. Here, we focus on chemokine CXCL12 and its receptor CXCR4 that have been widely characterized in peripheral tissues and delineate their main functions in the CNS. Extensive evidence supports CXCL12 as a key regulator for early development of the CNS. CXCR4 signaling is required for the migration of neuronal precursors, axon guidance/pathfinding and maintenance of neural progenitor cells (NPCs). In the mature CNS, CXCL12 modulates neurotransmission, neurotoxicity and neuroglial interactions. Thus, chemokines represent an inherent system that helps establish and maintain CNS homeostasis. In addition, growing evidence implicates altered expression of CXCL12 and CXCR4 in the pathogenesis of CNS disorders such as HIVassociated encephalopathy, brain tumor, stroke and multiple sclerosis (MS), making them the plausible targets for future pharmacological intervention.

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“…In neurons, internalization of gp120 and retrograde axonal transport are necessary for the toxic activity of gp120 (Bachis et al, 2003;Bachis et al, 2006). Therefore, we examined whether BDNF alters membrane-associated CXCR4.…”

Section: Bdnf Reduces Membrane Associated Cxcr4mentioning

confidence: 99%

Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain

et al. 2008

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Chemokine receptors, and in particular CXCR4 and CCR5 play a key role in the neuropathogenesis of Human Immunodeficiency Virus-1 (HIV)4 associated dementia (HAD). Thus, new insight into the expression of CXCR4 in the central nervous system may help develop therapeutic compounds against HAD. Brain-derived neurotrophic factor (BDNF) is neuroprotective in vitro against two strains of the HIV envelope protein gp120 that binds to CXCR4 or CCR5. Therefore, we examined whether BDNF modulates chemokine receptor expression in vivo. The content of CXCR4 mRNA and proteins was determined in the cerebral cortex and hippocampus of 6-month-old BDNF heterozygous mice and wild type littermates by using polymerase chain reaction and immunohistochemistry, respectively. BDNF heterozygous mice exhibited an increase in CXCR4 mRNA compared to wild type. Histological analyses revealed an up-regulation of CXCR4 immunoreactivity mainly in neurons. Most of these neurons were positive for TrkB, the BDNF receptor with a tyrosine kinase activity. Increases in CXCR4 mRNA levels were observed in 18-month-old BDNF heterozygous mice but not in 7 day-old mice, suggesting that the modulatory role of BDNF occurs only in mature animals. To determine whether BDNF affects also CXCR4 internalization, SH-SY5Y neuroblastoma cells were exposed to BDNF and cell surface CXCR4 levels were measured at various times. BDNF induced CXCR4 internalization within minutes. Lastly, BDNF heterozygous mice showed higher levels of CCR5 and CXCR3 mRNA than wild type in the cerebral cortex, hippocampus and striatum. Our data indicate that BDNF may modulate the availability of chemokine receptors implicated in HIV infection.

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Axonal Transport of Human Immunodeficiency Virus Type 1 Envelope Protein Glycoprotein 120 Is Found in Association with Neuronal Apoptosis

Cited by 83 publications

References 62 publications

Human Immunodeficiency Virus Type 1 Vpr Inhibits Axonal Outgrowth through Induction of Mitochondrial Dysfunction

Human Immunodeficiency Virus Type 1 Vpr Inhibits Axonal Outgrowth through Induction of Mitochondrial Dysfunction

Multiple roles of chemokine CXCL12 in the central nervous system: A migration from immunology to neurobiology

Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain

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