In vitro evidence for a dual role of tumor necrosis factor‐α in human immunodeficiency virus type 1 encephalopathy

Wilt, Susan G.; Milward, Elizabeth A.; Zhou, Jia Min; Nagasato, Kunihiko; Patton, Heather; Rusten, Ray; Griffin, Diane E.; O’Connor, Michael J.; Dubois‐Dalcq, Monique

doi:10.1002/ana.410370315

Cited by 138 publications

(59 citation statements)

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“…There is some in vitro evidence that microglial cells release various products which are toxic for brain cells, such as cytokines and neurotoxins. The AIDS dementia complex may result from the activity of one or more of these products (Benveniste, 1994;Gendelman et al, 1997;McEntee et al, 1992;Merrill and Martinez-Maza, 1993; Nottet et al, 1997; Persidsky et al, 1997; Vitkovic et al, 1994;Wilt et al, 1995). To determine whether the effects of the virus are direct or indirect, we conducted a longitudinal analysis of the CNS in SIV infected animals.…”

Section: Introductionmentioning

confidence: 99%

Viral load and neuropathology in the SIV model

Boche¹,

Khatissian²,

Gray³

et al. 1999

J Neurovirol

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To investigate neuropathological processes involved in HIV infection, a longitudinal analysis of central nervous system (CNS) changes was performed using the SIV-infected macaque model. Five animals were studied during the early phase and 13 during the asymptomatic and symptomatic phases. Histopathological analyses were performed on one cerebral ®xed hemisphere whereas on the other frozen hemisphere in situ hybridisation, immunohistochemistry and RT ± PCR were performed. Viral load was quanti®ed by in situ hybridisation, CD4 and CD8 T cell in®ltration by immunohistochemistry and mRNA cytokine expression (IL1b, IL2, IL6, TNFa, IFNg and TGF-b1) by semiquantitative RT ± PCR. As reported for HIV-infected humans, the neuropathological analysis of SIV infected animals revealed four distinct lesion pro®les: minimal changes, early encephalitis, leukoencephalopathy and encephalitis. No relationship was found between neuropathological ®ndings, numbers of SIV replicating cells and T cell in®ltration. CNS infection was found to be an early event characterised by glial activation, an increase in the level of IL1b, TNFa and IL6 mRNA expression. During the asymptomatic and symptomatic phases, IL6 and IL1b mRNAs increase coincided with gliosis and the development of myelin lesions. The absence of relationship between neuropathological ®ndings and viral load suggests that cerebral lesions are caused by an indirect mechanism. In¯ammatory cytokine pattern associated with severe lesions show the key role of glial activation in the SIV neuropathological process.

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Section: Introductionmentioning

confidence: 99%

Viral load and neuropathology in the SIV model

Boche¹,

Khatissian²,

Gray³

et al. 1999

J Neurovirol

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“…Depending on the particular virus, these pathways include direct cytopathic effects of the virus in oligodendrocytes, virus-induced inflammatory immune responses promoted by infected glia in the white matter, or molecular mimicry between virus and myelin antigens (43,56,57). In each of these responses, the activities of proinflammatory cytokines, interferons, and virus-induced genes play an important role in promoting or protecting against oligodendrocyte pathology (6,40,44,45,51,65). Therefore, the regulation of these activities in central nervous system (CNS) cells may be particularly important in controlling virus replication and virus-induced demyelinating processes.…”

mentioning

confidence: 99%

Critical Role for Protein Tyrosine Phosphatase SHP-1 in Controlling Infection of Central Nervous System Glia and Demyelination by Theiler's Murine Encephalomyelitis Virus

Massa

Ropka

Saha

et al. 2002

J Virol

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We previously characterized the expression and function of the protein tyrosine phosphatase SHP-1 in the glia of the central nervous system (CNS). In the present study, we describe the role of SHP-1 in virus infection of glia and virus-induced demyelination in the CNS. For in vivo studies, SHP-1-deficient mice and their normal littermates received an intracerebral inoculation of an attenuated strain of Theiler's murine encephalomyelitis virus (TMEV). At various times after infection, virus replication, TMEV antigen expression, and demyelination were monitored. It was found that the CNS of SHP-1-deficient mice uniquely displayed demyelination and contained substantially higher levels of virus than did that of normal littermate mice. Many infected astrocytes and oligodendrocytes were detected in both brains and spinal cords of SHP-1-deficient but not normal littermate mice, showing that the virus replicated and spread at a much higher rate in the glia of SHP-1-deficient animals. To ascertain whether the lack of SHP-1 in the glia was primarily responsible for these differences, glial samples from these mice were cultured in vitro and infected with TMEV. As in vivo, infected astrocytes and oligodendrocytes of SHP-1-deficient mice were much more numerous and produced more virus than did those of normal littermate mice. These findings indicate that SHP-1 is a critical factor in controlling virus replication in the CNS glia and virus-induced demyelination.

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“…We specifically focused on the role of TNF-␣ , a cytokine detected in acute lesions in EAE and MS, as an autocrine regulator of IL-12. Microglia are shown to express both p55 and p75 TNF receptors (11). We report that by blocking the action of autocrine TNF-␣ , with shu-TNF-R, we can inhibit LPS-induced production of IL-12 by human adult microglia.…”

Section: Introductionmentioning

confidence: 86%