Neuronal injury in hippocampus with human immunodeficiency virus transactivating protein, Tat

Maragos, William F.; Tillman, Philip A.; Jones, M. D.; Bruce‐Keller, Annadora J.; Roth, Susan; Bell, Jeanne E.; Nath, Avindra

doi:10.1016/s0306-4522(02)00713-3

Cited by 85 publications

(74 citation statements)

References 44 publications

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“…Previous studies indicate that HIV Tat is capable of mediating neuronal apoptosis through activation of proximal monocytoid cells and secretion of neurotoxins (59,60). Exposure of human fetal neurons to neurotoxic supernatants from HIV tat-transfected monocytoid cells (Tat S/N) led to a marked reduction in MAP-2 reactivity (Fig.…”

Section: Par-2 Expression and Activation On Neurons Reduces Tatinducementioning

confidence: 83%

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

Noorbakhsh

Vergnolle

McArthur

et al. 2005

The Journal of Immunology

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Proteinase-activated receptors (PARs), a newly discovered subgroup of G-protein coupled receptors, are widely expressed by neural cells, but their roles in the nervous system remain uncertain. In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia. The inflammatory cytokines TNF-α and IL-1β were also increased in HIV-1-associated dementia brains compared with patients without dementia (p < 0.05), but these same cytokines induced PAR-2 expression on neurons. Enhanced PAR-2 expression and subsequent activation prevented neuronal cell death and induction of the tumor suppressor, p53, caused by the HIV-encoded protein, Tat (p < 0.01). Intrastriatal implantation of a PAR-2 peptide agonist also inhibited Tat-induced neurotoxicity in a mouse model of HIV neuropathogenesis (p < 0.05). Moreover, PAR-2 null animals showed more severe neuroinflammation and neuronal loss caused by Tat neurotoxicity (p < 0.05). TNF-α protected wild-type neurons from Tat-related neurotoxicity, but in PAR-2-deficient neurons, the same concentrations of TNF-α were cytotoxic (p < 0.001). Thus, neuroinflammation can exert protective effects by which it induces PAR-2 expression with the ensuing abrogation of neuronal death.

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Section: Par-2 Expression and Activation On Neurons Reduces Tatinducementioning

confidence: 83%

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

Noorbakhsh

Vergnolle

McArthur

et al. 2005

The Journal of Immunology

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“…In a Tat transgenic model, there is marked glial cell activation accompanied by neuronal loss (13). Tat causes loss of selective populations of neurons in vitro and in vivo (14). Regions particularly susceptible to Tat neurotoxicity include the striatum (15), dentate gyrus, and the CA3 region of the hippocampus (16).…”

mentioning

confidence: 99%

HIV-1 Tat Protein Promotes Neuronal Dysfunction through Disruption of MicroRNAs

Chang

Mukerjee

Bagashev

et al. 2011

Journal of Biological Chemistry

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Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release from the infected cells and taken up by noninfected cells. Using microRNA array assay, we demonstrated that Tat deregulates the levels of several miRNAs. Interestingly, miR-34a was among the most highly induced miRNAs in Tat-treated neurons. Tat also decreases the levels of miR-34a target genes such as CREB protein as shown by real time PCR. The effect of Tat was neutralized in the presence of anti-miR-34a. Using in situ hybridization assay, we found that the levels of miR-34a increase in Tat transgenic mice when compared with the parental mice. Therefore, we conclude that deregulation of neuronal functions by HIV-1 Tat protein is miRNA-dependent.

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“…Accumulating evidence suggests that Tat is also an important mediator of neurotoxicity with lethal effects in the low nanamolar range. [47][48][49][50] Brain regions that are particularly susceptible to the toxic effects of Tat include the striatum, hippocampal dentate gyrus and the CA3 region of the hippocampus. 16,50,51 Although neurons are rarely, if ever, infected with HIV, neurons can be exposed to Tat following active release from HIV-infected lymphoid cells and glial cells.…”

Section: Neurotoxic Viral Proteinsmentioning

confidence: 99%

Cell death in HIV dementia

2005

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Many patients infected with human immunodeficiency virus type-1 (HIV-1) suffer cognitive impairment ranging from mild to severe (HIV dementia), which may result from neuronal death in the basal ganglia, cerebral cortex and hippocampus. HIV-1 does not kill neurons by infecting them. Instead, viral proteins released from infected glial cells, macrophages and/ or stem cells may directly kill neurons or may increase their vulnerability to other cell death stimuli. By binding to and/or indirectly activating cell surface receptors such as CXCR4 and the N-methyl-D-aspartate receptor, the HIV-1 proteins gp120 and Tat may trigger neuronal apoptosis and excitotoxicity as a result of oxidative stress, perturbed cellular calcium homeostasis and mitochondrial alterations. Membrane lipid metabolism and inflammation may also play important roles in determining whether neurons live or die in HIV-1-infected patients. Drugs and diets that target oxidative stress, excitotoxicity, inflammation and lipid metabolism are in development for the treatment of HIV-1 patients.

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Neuronal injury in hippocampus with human immunodeficiency virus transactivating protein, Tat

Cited by 85 publications

References 44 publications

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

HIV-1 Tat Protein Promotes Neuronal Dysfunction through Disruption of MicroRNAs

Cell death in HIV dementia

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