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Involvement of p300 in constitutive and HIV-1 Tat-activated expression of glial fibrillary acidic protein in astrocytes.

ABSTRACT: HIV-1 Tat protein is an important pathogenic factor in HIV-1-associated neurological diseases. One hallmark of HIV-1 infection of the central nervous system (CNS) is astrocytosis, which is characterized by elevated glial fibrillary acidic protein (GFAP) expression in astrocytes. We have shown that Tat activates GFAP expression in astrocytes [Zhou et al., (2004) Mol Cell Neurosci 27:296-305] and that GFAP is an important regulator of Tat neurotoxicity [Zou et al., (2007) Am J Pathol 171:1293-1935]. However, the underlying mechanisms for Tat-mediated GFAP up-regulation are not understood. In this study, we reported concurrent up-regulation of adenovirus E1a-associated 300 kDa protein p300 and GFAP in Tat-expressing human astrocytoma cells and primary astrocytes. We showed that p300 was indeed induced by Tat expression and HIV-1 infection and that the induction occurred at the transcriptional level through the cis-acting elements of early growth response 1 (egr-1) within its promoter. Using siRNA, we further showed that p300 regulated both constitutive and Tat-mediated GFAP expression. Moreover, we showed that ectopic expression of p300 potentiated Tat transactivation activity and increased proliferation of HIV-1-infected astrocytes, but had little effect on HIV-1 replication in these cells. Taken together, these results demonstrate for the first time that Tat is a positive regulator of p300 expression, which in turn regulates GFAP expression, and suggest that the Tat-Egr-1-p300-GFAP axis likely contributes to Tat neurotoxicity and predisposes astrocytes to be an HIV-1 sanctuary in the CNS.

SUBMITTER: Zou W

PROVIDER: S-EPMC2919602 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Involvement of p300 in constitutive and HIV-1 Tat-activated expression of glial fibrillary acidic protein in astrocytes.

Zou Wei W Wang Zhenyuan Z Liu Ying Y Fan Yan Y Zhou Betty Y BY Yang X Frank XF He Johnny J JJ

Glia 20101001 13

HIV-1 Tat protein is an important pathogenic factor in HIV-1-associated neurological diseases. One hallmark of HIV-1 infection of the central nervous system (CNS) is astrocytosis, which is characterized by elevated glial fibrillary acidic protein (GFAP) expression in astrocytes. We have shown that Tat activates GFAP expression in astrocytes [Zhou et al., (2004) Mol Cell Neurosci 27:296-305] and that GFAP is an important regulator of Tat neurotoxicity [Zou et al., (2007) Am J Pathol 171:1293-1935 ...[more]

PMID: 20578042

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Project description:Background and objectivesGlial fibrillary acidic protein (GFAP) antibodies can associate with an astrocytopathy often presenting as a meningoencephalitis. Visual involvement has been reported but scarcely defined. We describe 2 cases of GFAP astrocytopathy with predominant visual symptoms and present a systematic review of the literature.MethodsWe describe 2 patients with GFAP astrocytopathy from our neurology department. We performed a systematic review of the literature according to PRISMA guidelines, including all patients with this disease and available clinical data, focusing on visual involvement.ResultsPatient 1 presented with bilateral optic disc edema and severe sudden bilateral loss of vision poorly responsive to therapy. Patient 2 showed bilateral optic disc edema, headache, and mild visual loss with complete recovery after steroids. We screened 275 records and included 84 articles (62 case reports and 22 case series) for a total of 592 patients. Visual involvement was reported in 149/592 (25%), with either clinical symptoms or paraclinical test-restricted abnormalities. Bilateral optic disc edema was found in 80/159 (50%) of patients investigated with fundoscopy, among which 49/80 (61%) were asymptomatic. One hundred (100/592, 17%) reported visual symptoms, often described as blurred vision or transient visual obscurations. Optic neuritis was rare and diagnosed in only 6% of all patients with GFAP astrocytopathy, often without consistent clinical and paraclinical evidence to support the diagnosis. Four patients (including patient 1) manifested a severe, bilateral optic neuritis with poor treatment response. In patients with follow-up information, a relapsing disease course was more frequently observed in those with vs without visual involvement (35% vs 11%, p = 0.0035, OR 3.6 [CI 1.44-8.88]).DiscussionVisual system involvement in GFAP astrocytopathy is common and heterogeneous, ranging from asymptomatic bilateral optic disc edema to severe bilateral loss of vision, but optic neuritis is rare. GFAP CSF antibody testing should be considered in patients with encephalitis/meningoencephalitis or myelitis and bilateral optic disc edema, even without visual symptoms, and in patients with severe bilateral optic neuritis, especially when AQP4 antibodies are negative. Visual symptoms might associate with a higher relapse risk and help to identify patients who may require chronic immunosuppression.

Dataset Information

Involvement of p300 in constitutive and HIV-1 Tat-activated expression of glial fibrillary acidic protein in astrocytes.

Publications

Involvement of p300 in constitutive and HIV-1 Tat-activated expression of glial fibrillary acidic protein in astrocytes.

Similar Datasets

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