Reduction in glial immunity and neuropathology by a PAF antagonist and an MMP and TNFα inhibitor in SCID mice with HIV-1 encephalitis

Persidsky, Yuri; Limoges, Jenae; Rasmussen, Jennifer; Zheng, Jialin; Gearing, A. J. H.; Gendelman, Howard Eliot

doi:10.1016/s0165-5728(00)00454-9

Cited by 62 publications

(45 citation statements)

References 55 publications

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“…This confirms and extends previous findings that Tat-induced neuronal apoptosis was reduced with the use of anti-TNF-α neutralizing antibodies as well as suggestions that macrophages and microglia present in primary cultures of human fetal cortical neurons were the source of the TNF-α (New et al, 1998). Our findings are also consistent with findings that pentoxifylline, an inhibitor of TNF-α synthesis, protected against inflammation and cell loss observed with Tat infusions into mouse brain (Philippon et al, 1994), that in a murine model of HIV-1 encephalitis a TNF-α release inhibitor markedly reduced brain inflammation and neuronal injury (Persidsky et al, 2001), and that gene delivery of soluble tumor necrosis factor receptor protected neurons from Tat-induced cell death (Williams et al, 2005).…”

Section: Discussionsupporting

confidence: 90%

Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity

Buscemi

Ramonet

Geiger

2007

Neurobiology of Disease

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HIV-1 infection causes, with increasing prevalence, neurological disorders characterized in part by neuronal cell death. The HIV-1 protein Tat has been shown to be directly and indirectly neurotoxic. Here, we tested the hypothesis that a non-neurotoxic epitope of Tat can, through actions on immune cells, increase neuronal cell death. Tat 1-72 and a mutant Tat 1-72 lacking the neurotoxic epitope (Tat Δ31-61 ) concentration-dependently and markedly increased TNF-α production in macrophagelike differentiated human U937 and THP-1 cells, in mouse peritoneal macrophages and in mouse brain microglia. Tat 1-72 was but Tat Δ31-61 was not neurotoxic when applied directly to neurons. Supernatants from U937 cells treated with either Tat 1-72 or Tat Δ31-61 were neurotoxic and their immunoneutralization with an anti-TNF-α antibody decreased Tat 1-72 -and Tat Δ31-61 -induced neurotoxicity. Together, these results demonstrate that the neurotoxic epitope of Tat 1-72 is different from the epitope that is indirectly neurotoxic following production of TNF-α from immune cells, and suggest that therapeutic interventions against TNF-α might be beneficial against HIV-1 associated neurological disorders.

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Section: Discussionsupporting

confidence: 90%

Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity

Buscemi

Ramonet

Geiger

2007

Neurobiology of Disease

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“…Given this information, we speculate that in HAD, MMP inhibitors might prevent the influx of inflammatory cells through the BBB and help prevent damage to the neuropil's ECM. Indeed, such inhibitors have been effectively used in experimental autoimmune encephalitis, the animal model for multiple sclerosis (8,35) and the SCID mouse model for HIVE (45). Thus, treatment with MMP inhibitors may aid in repression of the immune effector responses of macrophages in addition to their direct effects on MMP activity.…”

Section: Discussionmentioning

confidence: 99%

Mononuclear Phagocyte Differentiation, Activation, and Viral Infection Regulate Matrix Metalloproteinase Expression: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

Ghorpade

Persidskaia

Suryadevara

et al. 2001

J Virol

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“…Pivotal roles for inflammatory processes in the neurodegenerative process in HIV-1 dementia are further suggested by studies showing that an inhibitor of TNF-a and MMPs, as well as a platelet-activating factor antagonist, reduce neuropathology in a mouse model of HIV-1 encephalitis. 162 …”

Section: Glial Cell Neurotoxins and Inflammationmentioning

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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Reduction in glial immunity and neuropathology by a PAF antagonist and an MMP and TNFα inhibitor in SCID mice with HIV-1 encephalitis

Cited by 62 publications

References 55 publications

Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity

Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity

Mononuclear Phagocyte Differentiation, Activation, and Viral Infection Regulate Matrix Metalloproteinase Expression: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

Cell death in HIV dementia

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