HIV-1 Tat Protein Promotes Neuronal Dysfunction through Disruption of MicroRNAs

Chang, Jian; Mukerjee, Ruma; Bagashev, Asen; Valle, Luis Del; Chabrashvili, Tinatin; Hawkins, Brian T.; He, Johnny J.; Sawaya, Bassel E.

doi:10.1074/jbc.m111.268466

Cited by 71 publications

(48 citation statements)

References 79 publications

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“…These findings demonstrate activation of DDR signaling and represent a potential mechanism triggering and driving miR-34a upregulation. In addition, the viral protein (HIV/SIV Tat) was also shown to induce the expression of miR-34a (43-44). Therefore, it is likely that Tat protein (direct effects of viral replication) and oxidative stress induced DDR (indirect effects of viral replication) can separately or collectively upregulate miR-34a expression in the colonic epithelium and LPL compartments.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated miR-34a–SIRT1–Acetyl p65 Axis Is a Potential Mediator of Immune Activation in the Colon during Chronic Simian Immunodeficiency Virus Infection of Rhesus Macaques

Mohan

Kumar

Lackner

et al. 2015

The Journal of Immunology

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Persistent gastrointestinal (GI) inflammation, a hallmark of progressive HIV/SIV infection causes disruption of the GI epithelial barrier, microbial translocation and generalized immune activation/inflammation driving AIDS progression. Apart from protein regulators, recent studies strongly suggest critical roles for microRNAs (miRNAs) in regulating and managing certain aspects of the inflammatory process. To examine their immunoregulatory role, we profiled miRNA expression in colon from 12 chronic SIV-infected and 4 control macaques. After applying multiple comparisons correction, 10 (3-up and 7-down) miRNAs showed differential expression. Most notably, miR-34a showed significant upregulation in both epithelial and lamina propria leukocyte (LPL) compartments. Intense γH2AX expression in colonic epithelium and LPL confirmed the contribution of DNA damage response in driving miR-34a upregulation. SIRT1 mRNA and protein decreased significantly in both colonic epithelium and LPL. Luciferase reporter assays validated rhesus macaque SIRT1 as a direct miR-34a target. Decreased SIRT1 expression was associated with constitutively enhanced expression of the transcriptionally active form of the p65 (acetylated on lysine 310) subunit of NFκB exclusively in the LPL compartment. The intensity and number of acetylated-p65+ cells was markedly elevated in LPLs of chronically SIV-infected macaques compared to uninfected controls and localized to increased numbers of IgA+ and IgG+ plasma cells. These findings provide new insights into the potential role of the miR-34a-SIRT1-p65 axis in causing hyperactivation of the intestinal B cell system. Our results point to a possible mechanism where the normal immunosuppressive function of SIRT1 is inhibited by elevated miR-34a expression resulting in constitutive activation of acetylated-p65 (lysine 310).

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Section: Discussionmentioning

confidence: 99%

Dysregulated miR-34a–SIRT1–Acetyl p65 Axis Is a Potential Mediator of Immune Activation in the Colon during Chronic Simian Immunodeficiency Virus Infection of Rhesus Macaques

Mohan

Kumar

Lackner

et al. 2015

The Journal of Immunology

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“…Tat is a multifunctional, viral regulatory protein that drives HIV transcription (Parada et al 1999). Tat protein is present in post-mortem brain tissue of HIV-positive individuals with HIV-associated-dementia or – encephalitis (Chang et al 2011; Hudson et al 2000; Nath et al 2000; Wesselingh et al 1993; Wiley et al 1996), and brain expression may persist despite highly active antiretroviral therapies (Agbottah et al 2006). Functional Tat protein is secreted from HIV-1 infected monocytes and glial cells to act at membrane-bound and intracellular targets, promoting cytokine production and infiltration (Nath et al 1991; Bruce-Keller et al 2001), oxidative stress (Kruman et al 1998) and neurotoxicity (Chang et al 1997; Ensoli et al 1990, 1993; Rayne et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Anxiety-like behavior of mice produced by conditional central expression of the HIV-1 regulatory protein, Tat

et al. 2013

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Rationale Human immunodeficiency virus (HIV) infection is associated with substantial increases in generalized anxiety. The HIV regulatory protein, transactivator of transcription (Tat), has been implicated in the neuropathogenesis related to HIV-1 infection. However, direct examination of the effect of Tat on behavioral measures of anxiety has not been demonstrated. Objective To identify whether expression of the Tat1-86 protein exerts dose-dependent and persistent anxiety-like effects in a whole animal model, the GT-tg bigenic mouse. Methods GT-tg mice and C57BL/6J controls were administered doxycycline in a dose- (0, 50, 100, or 125 mg/kg, i.p., for 7 days) or duration- (100 mg/kg, i.p., for 0, 1, 3, 5, or 14 days) dependent manner to induce Tat1-86 in brain. Mice were assessed for anxiety-like behavior in an open field, social interaction, or marble burying task 0, 7, and/or 14 days later. Central expression of Tat1-86 protein was verified with Western blot analyses. Results Doxycycline produced no effects on C57BL/6J controls that lacked the Tat1-86 transgene. Among GT-tg mice, doxycycline (100 mg/kg for 3, 5, or 7 days) significantly increased anxiety-like behavior in all tasks, commensurate with enhanced Western blot labeling of Tat1-86 protein in brain, displaying optimal effects with the 7-day regimen. Greater exposure to doxycycline (either 125 mg/kg for 7 days or 100 mg/kg for 14 days) impaired locomotor behavior; whereas, lower dosing (below 100 mg/kg) produced only transient increases in anxiety-like behavior. Conclusions Expression of HIV-1-Tat1-86 in GT-tg mouse brain produces exposure-dependent, persistent increases in anxiety-like behavior.

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“…49,50 Specifically, 69 microRNAs had a 2-fold change or greater response to treatment in neurons and a neuronal cell line. A reanalysis of the microarray data revealed that only 1 of the 69 microRNAs was expressed above a common detection threshold setting (negative control (background) signal plus 2 standard deviations).…”

Section: Microrna-seq Alignmentmentioning

confidence: 99%

Toward the promise of microRNAs – Enhancing reproducibility and rigor in microRNA research

2016

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The fields of applied and translational microRNA research have exploded in recent years as microRNAs have been implicated across a spectrum of diseases. MicroRNA biomarkers, microRNA therapeutics, microRNA regulation of cellular physiology and even xenomiRs have stimulated great interest, which have brought many researchers into the field. Despite many successes in determining general mechanisms of microRNA generation and function, the application of microRNAs in translational areas has not had as much success. It has been a challenge to localize microRNAs to a given cell type within tissues and assay them reliably. At supraphysiologic levels, microRNAs may regulate hosts of genes that are not the physiologic biochemical targets. Thus the applied and translational microRNA literature is filled with pitfalls and claims that are neither scientifically rigorous nor reproducible. This review is focused on increasing awareness of the challenges of working with microRNAs in translational research and recommends better practices in this area of discovery.

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HIV-1 Tat Protein Promotes Neuronal Dysfunction through Disruption of MicroRNAs

Cited by 71 publications

References 79 publications

Dysregulated miR-34a–SIRT1–Acetyl p65 Axis Is a Potential Mediator of Immune Activation in the Colon during Chronic Simian Immunodeficiency Virus Infection of Rhesus Macaques

Dysregulated miR-34a–SIRT1–Acetyl p65 Axis Is a Potential Mediator of Immune Activation in the Colon during Chronic Simian Immunodeficiency Virus Infection of Rhesus Macaques

Anxiety-like behavior of mice produced by conditional central expression of the HIV-1 regulatory protein, Tat

Toward the promise of microRNAs – Enhancing reproducibility and rigor in microRNA research

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