Presence of Tat and transactivation response element in spinal fluid despite antiretroviral therapy

Henderson, Lee A.; Johnson, Tory P.; Smith, Bryan; Reoma, Lauren B; Santamaria, Ulisses A.; Bachani, Muzna; DeMarino, Catherine; Barclay, Robert A.; Snow, Joseph; Sacktor, Ned; McArthur, Justin C.; Letendre, Scott; Steiner, Joseph P.; Kashanchi, Fatah; Nath, Avindra

doi:10.1097/qad.0000000000002268

Cited by 90 publications

(83 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this regard, Tat has been shown to be secreted through a number of different mechanisms, as previously reviewed which are dependent on residues at positions 11 and 49-51 and their interactions with phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P 2 ), a lipid in the plasma membrane (Rayne et al, 2010b). Tat secretion is a highly active process, and concentrations of extracellular Tat have been found (200 pg/ml to 6.5 ng/ml) in the cerebral spinal fluid (CSF) of HIV-1-infected patients who are well-suppressed on antiretroviral therapy (Johnson et al, 2013;Henderson et al, 2019). Within the central nervous system (CNS), extracellular Tat can recruit peripheral immune cells that has been shown to lead to low levels of chronic inflammation through activation of bystander cells and release of pro-inflammatory cytokines, such as interleukin (IL) 1 beta (IL-1β), IL-6, and monocyte chemoattractant protein 1 (MCP-1) from monocytes and macrophages (Hofman et al, 1994;Albini et al, 1998;Hudson et al, 2000;Pulliam et al, 2007;Rayne et al, 2010a;Bachani et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…As we have discussed, the biological relevance of Tat length within animal models may be another key distinguishing assay to assess differences in function. Animal models are crucial for understanding Tat, specifically due to Tat being measurably expressed in patients with low-toundetectable viremia or without detecting other HIV-1 proteins (Johnson et al, 2013;Henderson et al, 2019). Tat animal models often employ direct injection of Tat 72 or 86 into the brain (Aksenov et al, 2001(Aksenov et al, , 2003Cass et al, 2003;Fitting et al, 2008;Agrawal et al, 2012), however, this is not the only method of Tat exposure.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

HIV-1 Tat Length: Comparative and Functional Considerations

et al. 2020

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Length: Comparative and Functional Considerations

et al. 2020

View full text Add to dashboard Cite

“…Despite cART, regulatory HIV-1 proteins, including trans-activator of transcription (Tat) can be elevated in spinal fluid of aviremic individuals ( Henderson et al, 2019 ; Johnson et al, 2013 ) and secreted by infected cells ( Chopard et al, 2018 ; Debaisieux et al, 2012 ; Rayne et al, 2010 ; Schatz et al, 2018 ), disrupting bystander neuron function ( Chopard et al, 2018 ; Hategan et al, 2017 ). In fact, cART may increase Tat expression by attenuating feedback inhibition of proviral transcription ( Henderson et al, 2019 ; Johnson et al, 2013 ; Mbonye and Karn, 2017 ). To explore the role of Tat per se in the pathophysiology of HIV, the present ( Bruce-Keller et al, 2008 ) and another closely related Tat transgenic model ( Kim et al, 2003 ) have been extensively used.…”

Section: Introductionmentioning

confidence: 99%

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

Nass

Hahn

McLane

et al. 2020

Brain, Behavior, & Immunity - Health

View full text Add to dashboard Cite

HIV-1 selectively disrupts neuronal integrity within specific brain regions, reflecting differences in viral tropism and/or the regional differences in the vulnerability of distinct neuronal subpopulations within the CNS. Deficits in prefrontal cortex (PFC)-mediated executive function and the resultant loss of behavioral control are a particularly debilitating consequence of neuroHIV. To explore how HIV-1 disrupts executive function, we investigated the effects of 48 h, 2 and/or 8 weeks of HIV-1 Tat exposure on behavioral control, synaptic connectivity, and neuroimmune function in the anterior cingulate cortex (ACC) and associated cortico-basal ganglia (BG)-thalamocortical circuitry in adult, Tat transgenic male mice. HIV-1 Tat exposure increased novelty-exploration in response to novel food, flavor, and environmental stimuli, suggesting that Tat triggers increased novelty-exploration in situations of competing motivation (e.g., drive to feed or explore vs. fear of novel, brightly lit open areas). Furthermore, Tat induced adaptability in response to an environmental stressor and pre-attentive filtering deficits. The behavioral insufficiencies coincided with decreases in the inhibitory pre- and post-synaptic proteins, synaptotagmin 2 and gephyrin, respectively, in the ACC, and alterations in specific pro- and anti-inflammatory cytokines out of 23 assayed. The interaction of Tat exposure and the resultant time-dependent, selective alterations in CCL4, CXCL1, IL-12p40, and IL-17A levels in the PFC predicted significant decreases in adaptability. Tat decreased dendritic spine density and cortical VGLUT1 inputs, while increasing IL-1β, IL-6, CCL5, and CCL11 in the striatum. Alternatively, IL-1α, CCL5, and IL-13 were decreased in the mediodorsal thalamus despite the absence of synaptic changes. Thus, HIV-1 Tat appears to uniquely and systematically disrupt immune regulation and the inhibitory and excitatory synaptic balance throughout the ACC-BG-thalamocortical circuitry resulting in a loss of behavioral control.

show abstract

“…Astrocytes are extensively infected with HIV-1, and these cells also act as a “safe heaven” for the latent form of the virus [ 6 , 7 ]. In addition, the clinical reports also reveal the presence of HIV-1 Tat protein in the cerebrospinal fluid (CSF) from the infected patients successfully treated with cART [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Novel role of mortalin in attenuating HIV-1 Tat-mediated astrogliosis

Priyanka

Wadhwa

Chaudhuri

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background In human immunodeficiency virus-1 (HIV-1) infection, activation of astrocytes induces imbalance in physiological functions due to perturbed astrocytic functions that unleashes toxicity on neurons. This leads to inflammatory response finally culminating into neurocognitive dysfunction. In neuroAIDS, HIV-1 protein, transactivator of transcription (Tat) is detected in the cerebrospinal fluid of infected patients. Mortalin, a multifunctional protein, has anti-inflammatory role following its activation in various stress conditions. Recent studies demonstrate downregulation of mortalin in neurodegenerative diseases. Here, we explored the mechanisms of mortalin in modulating HIV-1 Tat-mediated neuroinflammation. Methods Expression of mortalin in autopsy section in normal and diseased individuals were examined using immunohistochemistry. To decipher the role of mortalin in HIV-1 Tat-induced activation, human fetal brain-derived astrocytes were transiently transfected with Tat and mortalin using expression vectors. HIV-1 Tat-mediated damage was analyzed using RT-PCR and western blotting. Modulatory role of mortalin was examined by coexpressing it with Tat, followed by examination of mitochondrial morphodynamics using biochemical assay and confocal and electron microscopy. Extracellular ATP release was monitored using luciferase assay. Neuroinflammation in astrocytes was examined using flow cytometry, dye based study, immunocytochemistry, immunoprecipitation, and western blotting. Indirect neuronal damage was also analyzed. Results HIV-1 Tat downregulates the expression of mortalin in astrocytes, and this is corroborated with autopsy sections of HIV-1 patients. We found that overexpression of mortalin with Tat reduced inflammation and also rescued astrocytic-mediated neuronal death. Using bioinformatics, we discovered that binding of mortalin with Tat leads to Tat degradation and rescues the cell from neuroinflammation. Blocking of proteosomal pathway rescued the Tat degradation and revealed the ubiquitination of Tat. Conclusion Overall, our data demonstrated the protective role of mortalin in combating HIV-1 Tat-mediated damage. We also showed that mortalin could degrade Tat through direct binding with HIV-1 Tat. Overexpression of mortalin in the presence of Tat could significantly reduce cytotoxic effects of Tat in astrocytes. Indirect neuronal death was also found to be rescued. Our in vitro findings were validated as we found attenuated expression of mortalin in the autopsy sections of HIV-1 patients.

show abstract

Presence of Tat and transactivation response element in spinal fluid despite antiretroviral therapy

Cited by 90 publications

References 96 publications

HIV-1 Tat Length: Comparative and Functional Considerations

HIV-1 Tat Length: Comparative and Functional Considerations

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

Novel role of mortalin in attenuating HIV-1 Tat-mediated astrogliosis

Contact Info

Product

Resources

About