Human immunodeficiency virus-1 infection of the nervous system: An autopsy study of 268 adult, pediatric, and fetal brains

Kure, Katsuhiro; Llena, Josefina F.; Lyman, William D.; Soeiro, Ruy; Weidenheim, Karen M.; Hirano, Atsushi; Dickson, Dennis W.

doi:10.1016/0046-8177(91)90293-x

Cited by 260 publications

(120 citation statements)

References 36 publications

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“…However, an anomaly exists between the number of virus antigen-positive cells in the brain parenchyma and the extent of the neuropathology (Georgsson et al, 1989). This disparity is not con®ned to ruminant lentiviruses; similar observations have also been made in HIV-1 and SIV encephalopathies (Gabuzda et al, 1986;Wiley et al, 1986;Kure et al, 1991;Brinkman et al, 1993;Nuovo and Al®eri, 1996).…”

Section: Introductionsupporting

confidence: 60%

Phenotypic characterisation and infection of ovine microglial cells with Maedi-Visna Virus

Ebrahimi¹,

Allsopp²,

Fazakerley³

et al. 2000

J Neurovirol

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Maedi-Visna Virus (MVV) infection of the central nervous system (CNS) results in pathological changes, the mechanisms of which are poorly understood. MVV preferentially infects cell of the monocyte/macrophage lineage in vivo. The neuroparenchymal microglial cells are the resident tissue macrophages in the CNS and therefore likely targets for MVV infection. However, no information is currently available on the susceptibility of these cells to MVV infection or their contribution to neuropathological changes as a result of MVV infection. Highly enriched primary ovine microglial cell cultures were set up from brain tissues of lambs. These cells were amoeboid or bipolar with spikes, a morphology consistent with microglial cells of other species, and stained positive for CD1, CD11a, CD11c, CD14, MHC-class I, MHC-class II, and b-N-acetyl galactose, but not with markers of astrocytes or oligodendrocytes. These sheep microglial cells were permissive for MVV infection. Productive MVV infection resulted in selective transcriptional upregulation of the pro-in¯ammatory cytokines TNFa and IL-6. In contrast, there was no change in levels of transcripts for TGFb1, IL-1b, GM-CSF, IL-10, or IL-12. These data provide the ®rst evidence that ovine microglial cells can support productive infection with MVV, and that this leads to a selective upregulation of proin¯ammatory cytokines. These may contribute to visna neuropathology. Journal of NeuroVirology (2000) 6, 320 ± 328.

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Section: Introductionsupporting

confidence: 60%

Phenotypic characterisation and infection of ovine microglial cells with Maedi-Visna Virus

Ebrahimi¹,

Allsopp²,

Fazakerley³

et al. 2000

J Neurovirol

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“…the spread of neurodegeneration seen in ADC despite the poor correlation between viral load and neuronal atrophy in these individuals (Kure et al, 1991).…”

Section: Gp120 Is Transported To Distal Neuronsmentioning

confidence: 99%

“…HIV-infected cells consist almost exclusively of perivascular macrophages and microglia (Lee et al, 1993;Persidsky and Gendelman, 2003), and viral load does not always correlate with the clinical manifestation of the disease (Kure et al, 1991). Thus, an intriguing and yet unresolved issue in the neuropathogenesis of HIV is how relatively few infected cells can produce pronounced neuronal dysfunction and cause widespread neuronal atrophy.…”

Section: Introductionmentioning

confidence: 99%

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

Bachis

Aden

Nosheny

et al. 2006

Journal of Neuroscience

128

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Patients infected by human immunodeficiency virus type 1 (HIV-1) develop acquired immune deficiency syndrome-associated dementia complex (ADC), a disorder characterized by a broad spectrum of motor impairments and cognitive deficits. The number of cells in the brain that are productively infected by HIV-1 is relatively small and consists predominantly of macrophages and microglia, yet HIV-1 causes widespread neuronal loss. A better understanding of the pathogenic mechanisms mediating HIV-1 neurotoxicity is crucial for developing effective neuroprotective therapies against ADC. The HIV-1 envelope glycoprotein 120 (gp120), which is shed from the virus, is one of the agents causing neuronal cell death. However, the cellular mechanisms underlying its neurotoxic effect remain unclear. We report that 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. Cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, 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 because AMD3100, a selective CXCR4 inhibitor, blocked both events. Furthermore, colchicine or nocodazole, two inhibitors of intracellular trafficking, abolished gp120-mediated apoptosis in distal areas. These results indicate that axonal transport of gp120 might play a role in HIV-1-mediated widespread neuronal cell death.

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“…HIV-1 has been shown to penetrate the central nervous system (CNS) and replicate in brain macrophages and microglia (Kure et al, 1991;Bagasra et al, 1996). Moreover, the CNS provides a sanctuary for the virus in the body as a result of insufficient antiretroviral drug delivery through the blood-brain barrier (BBB) (Pialoux et al, 1997).…”

mentioning

confidence: 99%

Abcg2/Bcrp1 Mediates the Polarized Transport of Antiretroviral Nucleosides Abacavir and Zidovudine

Pan¹,

Giri

Elmquist

2007

Drug Metab Dispos

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ABSTRACT:The bioavailability and targeted distribution of abacavir (ABC) and zidovudine (AZT) to viral reservoirs may be influenced by efflux transporters. The purpose of this study was to characterize the interaction of these nucleoside reverse transcriptase inhibitors with the Abcg2/Bcrp1 transporter, the murine homolog of human breast cancer resistance protein (BCRP), using a Bcrp1-trans- (6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1,2:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester) was observed with an EC 50 of 121 ؎ 5 nM for ABC and 19.2 ؎ 1.5 nM for AZT (Hill coefficient ϳ3-6). Probenecid, an organic anion inhibitor known to influence AZT biodistribution, had no effect on cellular accumulation in the Bcrp1 model. These studies characterize the Bcrp1-mediated transport of ABC and AZT and show that prototypical BCRP inhibitors GF120918 and Ko143 can inhibit the Bcrp1-mediated transport of these important antiretroviral compounds. The functional expression of BCRP at critical barriers, such as the intestinal enterocytes, brain capillary endothelium, and target lymphocytes, could influence the bioavailability and targeted delivery of these drugs to sanctuary sites.

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Human immunodeficiency virus-1 infection of the nervous system: An autopsy study of 268 adult, pediatric, and fetal brains

Cited by 260 publications

References 36 publications

Phenotypic characterisation and infection of ovine microglial cells with Maedi-Visna Virus

Phenotypic characterisation and infection of ovine microglial cells with Maedi-Visna Virus

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

Abcg2/Bcrp1 Mediates the Polarized Transport of Antiretroviral Nucleosides Abacavir and Zidovudine

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