HIV-I-associated central nervous system dysfunction

Krebs, Fred C.; Ross, Heather L.; McAllister, John; Wigdahl, Brian

doi:10.1016/s1054-3589(00)49031-9

Cited by 68 publications

(39 citation statements)

References 327 publications

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“…These resident macrophages are the primary target of HIV-1 productive infection within the central nervous system (33), which results in a wide range of neurological complications (18,26). Our findings reveal the ability of CTIP2 to specifically act as a potent inhibitor of Tat function, leading to repression of viral replication.…”

mentioning

confidence: 82%

Recruitment of Tat to Heterochromatin Protein HP1 via Interaction with CTIP2 Inhibits Human Immunodeficiency Virus Type 1 Replication in Microglial Cells

Rohr

Lecestre

Chasserot‐Golaz³

et al. 2003

J Virol

103

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The Tat protein of human immunodeficiency virus type 1 (HIV-1) plays a key role as inducer of viral gene expression. We report that Tat function can be potently inhibited in human microglial cells by the recently described nuclear receptor cofactor chicken ovalbumin upstream promoter transcription factor-interacting protein 2 (CTIP2). Overexpression of CTIP2 leads to repression of HIV-1 replication, as a result of inhibition of Tat-mediated transactivation. In contrast, the related CTIP1 was unable to affect Tat function and viral replication. Using confocal microscopy to visualize Tat subcellular distribution in the presence of the CTIPs, we found that overexpression of CTIP2, and not of CTIP1, leads to disruption of Tat nuclear localization and recruitment of Tat within CTIP2-induced nuclear ball-like structures. In addition, our studies demonstrate that CTIP2 colocalizes and associates with the heterochromatin-associated protein HP1␣. The CTIP2 protein harbors two Tat Regulation of human immunodeficiency virus type 1 (HIV-1) gene transcription is governed by a complex interplay between chromatin-associated proviral DNA, host cell proteins, and the virus-encoded transactivator protein, Tat. In the immediateearly phase of HIV infection, cellular transcription factors activate transcription from the viral long terminal repeat (LTR) (for a review, see references 24 and 32). This leads to the accumulation of the viral protein Tat that leads to a potent increase in transcription and is required for viral replication and a high viral load (for a review, see reference 37). The ability of Tat to function as a transcriptional activator is mediated by multiple interactions with cellular proteins and requires the concerted action of Tat and upstream nuclear factors that bind to the Sp1 and B region of the LTR (for reviews, see references 16 and 17). Tat forms a ternary complex with the coactivators P/CAF and p300 which helps Tat activate transcription of integrated viral DNA and derepress the HIV-1 chromatin structure in response to histone acetylation (3). Mechanisms that inhibit HIV-1 LTR expression are largely unexplored. Recent studies have shown that Tat activation can be inhibited by the overexpression of the host factors YY1 and LSF, which recruit histone deacetylase 1 to the LTR (20).We have previously reported that Tat also interacts and cooperates with an orphan member of the nuclear receptor superfamily, the chicken ovalbumin upstream promoter transcription factor (COUP-TF) that together with Sp1 activates HIV-1 LTR-driven transcription (34,35). Members of the COUP-TF family were recently shown to bind to novel and related zinc finger proteins and COUP TF-interacting protein 1 (CTIP1) and CTIP2. CTIP1 was found to induce transcriptional silencing by relocating COUP-TF to distinct nuclear structures, possibly associated with heterochromatic regions (1). These studies revealed a novel mechanism for transcriptional repression, by recruitment of a transcription factor to distinct nuclear loci, instead of acting t...

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mentioning

confidence: 82%

Recruitment of Tat to Heterochromatin Protein HP1 via Interaction with CTIP2 Inhibits Human Immunodeficiency Virus Type 1 Replication in Microglial Cells

Rohr

Lecestre

Chasserot‐Golaz³

et al. 2003

J Virol

103

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“…Considerable experimental evidence indicates BBB damage in human immunodeficiency virus-1 (HIV-1) infection (McArthur et al, 1992;Petito and Cash, 1992;Giovannoni et al, 1998). Such alterations were shown in pathologic studies (Rhodes and Ward, 1991;Krebs et al, 2000), CSF studies (Singer et al, 1994), and by dynamic magnetic resonance imaging (Avison et al, 2002). Disruption of the BBB appears to be critical for HIV-1 trafficking into the brain (Wu et al, 2000) and the development of HIV-1-associated central nervous system (CNS) complications.…”

Section: Introductionmentioning

confidence: 99%

Signaling Mechanisms of HIV-1 Tat-Induced Alterations of Claudin-5 Expression in Brain Endothelial Cells

András

Peng

Tian

et al. 2005

J Cereb Blood Flow Metab

121

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Exposure of brain microvascular endothelial cells (BMEC) to human immunodeficiency virus-1 (HIV-1) Tat protein can decrease expression and change distribution of tight junction proteins, including claudin-5. Owing to the importance of claudin-5 in maintaining the blood-brain barrier (BBB) integrity, the present study focused on the regulatory mechanisms of Tat-induced alterations of claudin-5 mRNA and protein levels. Real-time reverse-transcription-polymerase chain reaction revealed that claudin-5 mRNA was markedly diminished in BMEC exposed to Tat. However, U0126 (an inhibitor of mitogen-activated protein kinase kinase1/2, MEK1/2) protected against this effect. In addition, inhibition of the vascular endothelial growth factor receptor type 2 (VEGFR-2) by SU1498, phosphatidylinositol-3 kinase (PI-3 K) by LY294002, nuclear factor-jB (NF-jB) by peptide SN50, and intracellular calcium by BAPTA/AM partially prevented Tat-mediated alterations in claudin-5 protein levels and immunoreactivity patterns. In contrast, inhibition of protein kinase C did not affect claudin-5 expression in Tat-treated cells. The present findings indicate that activation of VEGFR-2 and multiple redox-regulated signal transduction pathways are involved in Tat-induced alterations of claudin-5 expression. Because claudins constitute the major backbone of tight junctions, the present data are relevant to the disturbances of the BBB in the course of HIV-1 infection.

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“…Astrocytes suffer dysregulation by neighboring cells leading to viral transmission and productive replication in adjoining microglia, which contribute to neuropathogensis. Meantime, astrocytes are exposed continuously to HIV-1 particles, viral proteins (such as Nef and Tat), cytokines, and neurotoxic substances secreted by HIV-1 infected microglia or macrophages (Lipton, 1994;Vesce et al, 1997;Brenneman et al, 2000;Krebs et al, 2000;Dou et al, 2006;Jayadev et al, 2007). In this study, we employed VSV pseudotyped M-tropical HIV-1 YU2 strain to circumvent astrocytic receptor restrictions and trigger the intracellular entry of virus RNA.…”

Section: Discussionmentioning

confidence: 99%

HIV-1-Infected Astrocytes and the Microglial Proteome

Wang

Gong

Liu

et al. 2008

J Neuroimmune Pharmacol

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The human immunodeficiency virus (HIV) invades the central nervous system early after viral exposure but causes progressive cognitive, behavior, and motor impairments years later with the onset of immune deficiency. Although in the brain, HIV preferentially replicates productively in cells of mononuclear phagocyte (MP; blood borne macrophage and microglia), astrocytes also can be infected, at low and variable frequency, particularly in patients with encephalitis. Among their many functions, astrocytes network with microglia to provide the first line of defense against microbial infection; however, very little is known about its consequences on MP. Here, we addressed this question using co-culture systems of HIV infected mouse astrocytes and microglia. Pseudotyped vesicular stomatis virus/HIV was used to circumvent absence of viral receptors and ensure cell genotypic uniformity for studies of intercellular communication. The study demonstrated that infected astrocytes show modest changes in protein elements as compared to uninfected cells. In contrast, infected astrocytes induce robust changes in the proteome of HIV-1 infected microglia. Accelerated cell death and redox proteins, amongst others, were produced in abundance. The observations confirmed the potential of astrocytes to influence the neuropathogenesis of HIV-1 infection by specifically altering the neurotoxic potential of infected microglia and in this manner, disease progression.

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HIV-I-associated central nervous system dysfunction

Cited by 68 publications

References 327 publications

Recruitment of Tat to Heterochromatin Protein HP1 via Interaction with CTIP2 Inhibits Human Immunodeficiency Virus Type 1 Replication in Microglial Cells

Recruitment of Tat to Heterochromatin Protein HP1 via Interaction with CTIP2 Inhibits Human Immunodeficiency Virus Type 1 Replication in Microglial Cells

Signaling Mechanisms of HIV-1 Tat-Induced Alterations of Claudin-5 Expression in Brain Endothelial Cells

HIV-1-Infected Astrocytes and the Microglial Proteome

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