HIV-1 Tat increases BAG3 via NF-κB signaling to induce autophagy during HIV-associated neurocognitive disorder

Wu, Xiaoyan; Dong, Huaqian; Xiang, Yu‐Tao; Zhong, Li; Cao, Tiantian; Xu, Qiping; Wang, Jun; Zhang, Yu; Xu, Jinhong; Wang, Wei; Wang, Qiang; Liu, Ying; Wang, Shuhui; Shao, Yiming; Huang, Xing

doi:10.1080/15384101.2018.1480219

Cited by 21 publications

(16 citation statements)

References 34 publications

(36 reference statements)

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“…Additionally, experiments performed in transgenic mice that specifically express HIV-1 Tat protein, have confirmed that transgenic mice without HIV-1 infection but expressing HIV-1 Tat exhibit similar recognition and behavioral changes as HAND patients (Kim et al, 2003). Furthermore, our former works have demonstrated that HIV-1 Tat may participate in the pathogenesis of HAND (Ye et al, 2017; Wu et al, 2018). Accordingly, we surmised that the expression of FOXO3 in neurons potentially regulated by HIV-1 Tat in HAND.…”

Section: Discussionmentioning

confidence: 99%

Role of FOXO3 Activated by HIV-1 Tat in HIV-Associated Neurocognitive Disorder Neuronal Apoptosis

et al. 2019

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There are numerous types of pathological changes in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), including apoptosis of neurons. HIV-1 transactivator of transcription (Tat) protein, which is encoded by HIV-1, may promote apoptosis in HAND. Forkhead box O3 (FOXO3) is a multispecific transcription factor that has roles in many biological processes, including cellular apoptosis. The aim of this study was to determine whether FOXO3 is activated by HIV-1 Tat and to investigate its role in neuronal apoptosis in HAND. We employed tissue staining and related molecular biological experimental methods to confirm our hypothesis. The in vivo experimental results demonstrated that the expression of nuclear FOXO3 increased in the apoptotic neurons of the cerebral cortexes of rhesus macaques infected with simian human immunodeficiency virus (SHIV). The in vitro investigation showed that HIV-1 Tat activated FOXO3, causing it to move from the cytoplasm to the nucleus via the c-Jun N-terminal kinase (JNK) signaling pathway in SH-SY5Y cells. Moreover, FOXO3 down-regulated expression of the anti-apoptosis gene B-cell lymphoma 2 (Bcl-2) and up-regulated the expression of the pro-apoptosis gene Bcl-2-like 11 (Bim) after entering the nucleus, eventually causing cellular apoptosis. Finally, reduction of nuclear FOXO3 reversed cellular apoptosis. Our results suggest that HIV-1 Tat induces FOXO3 to translocate from the cytoplasm to the nucleus via the JNK signaling pathway, leading to neuronal apoptosis. Agents targeting FOXO3 may provide approaches for restoring neuronal function in HAND.

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Section: Discussionmentioning

confidence: 99%

Role of FOXO3 Activated by HIV-1 Tat in HIV-Associated Neurocognitive Disorder Neuronal Apoptosis

et al. 2019

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“…The activation of NFkB often acts as an initiating signal for the transcription of HIV-1, and targeting this signaling pathway could prevent ongoing low-level neurodegeneration by disturbing HIV-1's ability to sense immune cell activation [89]. Inhibition of NF-κB activity can reverse neuronal autophagy induced by Tat [90]. We recently reported that HIV-1 Vpr-induced proin ammatory response and apoptotic cell death are mediated through the NF-kB activation in astrocytes [91].…”

Section: Discussionmentioning

confidence: 99%

7,8-dihydroxyflavone Improves Neuropathological Changes in the Brain of Tg26 Mice, A Model for HIV-associated Neurocognitive Disorder

Bryant

Andhavarapu

Bever

et al. 2020

Preprint

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Background: The combined antiretroviral therapy (cART) era has significantly increased the lifespan of HIV patients, turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). Therefore, research is currently seeking improved treatment for this complication of HIV. In HIV+ patients, low levels of brain derived neurotrophic factor (BDNF) has been associated with worse neurocognitive impairment. Hence, BDNF administration has been gaining relevance as a possible adjunct therapy for HAND. However, systemic administration of BDNF is impractical because of poor pharmacological profile.Methods: We investigated the neuroprotective effects of BDNF-mimicking 7,8 dihydroxyflavone (DHF), a bioactive high-affinity TrkB agonist, in the memory-involved hippocampus and brain cortex of Tg26 mice, a murine model for HAND. We immunohistochemically stained brain tissue sections from vehicle-treated wild type (WT), vehicle-treated Tg26, and DHF (5 mg/kg, i.p)-treated Tg26 mice to examine activation of TrkB and downstream signaling, expression of HIV-1 chemokine co-receptors CXCR4 and CCR5, neuroinflammation, and mitochondrial damage. A one-way ANOVA with a Bonferroni Comparison post-hoc test was performed to analyze the data sets. Results: In the brain regions of Tg26 mice, we observed astrogliosis, increased CXCR4 and CCR5 expression, neuroinflammation, and mitochondrial damage. Hippocampi and cortices of DHF treated mice exhibited a reversal of these pathological changes, suggesting the therapeutic potential of DHF in HAND. Our data indicates that DHF increases the phosphorylation of TrkB, providing new insights about the role of the TrkB-Akt-NFkB signaling pathway in mediating these pathological hallmarks.Conclusions: Our study provides an overview of how targeting BDNF-TrkB signaling in the pathophysiology of HAND may be relevant for future therapies, and sheds light on 7,8 Dihydroxyflavone as a potential adjunct therapeutic agent to current antiviral therapy.

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“…Additionally, it has been shown that Nef-protein, encoded by human immunodeficiency virus type 1 (HIV-1), blocks the fusion of the autophagosome with the lysosome, thereby keeping the virus inside cells [ 56 ]. Later, the virus found to encodes the protein Tat promote autophagy in neuronal cells [ 57 ] and gliomas via BAG3 signaling [ 57 ].…”

Section: Unfolded Protein Response (Upr): One Process Two Impactsmentioning

confidence: 99%

Oncolytic Virus-Induced Autophagy in Glioblastoma

Kamynina

Tskhovrebova

Fares

et al. 2021

Cancers

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Autophagy is a catabolic process that allows cells to scavenge damaged organelles and produces energy to maintain cellular homeostasis. It is also an effective defense method for cells, which allows them to identify an internalized pathogen and destroy it through the fusion of the autophagosome and lysosomes. Recent reports have demonstrated that various chemotherapeutic agents and viral gene therapeutic vehicles provide therapeutic advantages for patients with glioblastoma as monotherapy or in combination with standards of care. Despite nonstop efforts to develop effective antiglioma therapeutics, tumor-induced autophagy in some studies manifests tumor resistance and glioma progression. Here, we explore the functional link between autophagy regulation mediated by oncolytic viruses and discuss how intracellular interactions control autophagic signaling in glioblastoma. Autophagy induced by oncolytic viruses plays a dual role in cell death and survival. On the one hand, autophagy stimulation has mostly led to an increase in cytotoxicity mediated by the oncolytic virus, but, on the other hand, autophagy is also activated as a cell defense mechanism against intracellular pathogens and modulates antiviral activity through the induction of ER stress and unfolded protein response (UPR) signaling. Despite the fact that the moment of switch between autophagic prosurvival and prodeath modes remains to be known, in the context of oncolytic virotherapy, cytotoxic autophagy is a crucial mechanism of cancer cell death.

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HIV-1 Tat increases BAG3 via NF-κB signaling to induce autophagy during HIV-associated neurocognitive disorder

Cited by 21 publications

References 34 publications

Role of FOXO3 Activated by HIV-1 Tat in HIV-Associated Neurocognitive Disorder Neuronal Apoptosis

Role of FOXO3 Activated by HIV-1 Tat in HIV-Associated Neurocognitive Disorder Neuronal Apoptosis

7,8-dihydroxyflavone Improves Neuropathological Changes in the Brain of Tg26 Mice, A Model for HIV-associated Neurocognitive Disorder

Oncolytic Virus-Induced Autophagy in Glioblastoma

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