Human immunodeficiency virus-1 Tat exerts its neurotoxic effects by downregulating Sonic hedgehog signaling

Khan, Irfan; Worrad, Arthur H; Singh, Meera V.; Maggirwar, Sanjay B.; Singh, Vir B.

doi:10.1007/s13365-022-01061-8

Cited by 6 publications

(1 citation statement)

References 36 publications

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“…HIV envelope protein gp120 incites the activation of chemokine receptors on neurons and triggers the elevation of intracellular Ca 2+ leading to apoptosis [20]. The HIV transcriptional activator protein Tat can also bind LRP in neurons, causing LRP internalization and inducing apoptosis [21,22]; recently it has been reported that Tat exerts its neurotoxic effects by downregulating Sonic hedgehog signaling [23]. Furthermore, because ART does not impact levels of HIV Tat and the CNS is not accessible to the ART regiments, Tat has been regarded as a mediator of HAND [24].…”

Section: Introductionmentioning

confidence: 99%

Integrated Analysis of the miRNA-mRNA Regulatory Network Involved in HIV-Associated Neurocognitive Disorder

2022

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HIV-associated neurocognitive disorder (HAND) is an array of neurocognitive changes associated with HIV infection, and the roles of microRNAs in HAND have not yet been completely revealed. Based on published data and publicly available databases, we constructed an integrated miRNA-mRNA network involved in HAND. Bioinformatics analyses, including gene ontology, network analysis, and KEGG pathway analysis, were applied for further study of the network and the genes of the network. The axon guidance KEGG pathway, three genes NTNG1, EFNB2, CXCL12, and 17 miRNAs which regulate these genes are spotlighted in our study. This study provides new perspectives to the knowledge of miRNAs’ roles in the progression of HAND, and our findings provide potential therapeutic targets and clues of HAND.

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Section: Introductionmentioning

confidence: 99%

Integrated Analysis of the miRNA-mRNA Regulatory Network Involved in HIV-Associated Neurocognitive Disorder

2022

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Compensatory reactions of B cells in response to chronic HIV‐1 Tat exposure

Valyaeva,

Tikhomirova,

Feng

et al. 2024

Journal Cellular Physiology

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Patients infected with human immunodeficiency virus‐1 (HIV‐1) have an increased incidence of B‐cell lymphoma, even though HIV‐1 does not infect B cells. The development of B‐cell lymphomas appears to be related to the action of the HIV‐1 transactivator protein (Tat), which is released from HIV‐infected cells and penetrates uninfected B cells, affecting host cell gene expression. Upon chronic HIV‐1 infection, Tat acts on the cells for a long time, probably allowing the cells to adapt to the presence of the viral protein. The aim of this work was to identify and study the mechanism of adaptation of cells to prolonged (chronic) exposure to HIV‐1 Tat. We performed a comparative analysis of cells expressing Tat under the action of either an inducible promoter or a constitutive promoter, allowing us to model acute and chronic Tat effects, respectively. We found that the acute action of Tat leads to the suppression of cell proliferation, probably due to the downregulation of genes associated with replication and protein synthesis. In the case of chronic action of Tat, cell proliferation was restored and the expression of genes associated with the implementation of protective (antiviral) functions of the cell was increased. Analysis using proteasome inhibitors showed that in the case of chronic action, intense Tat proteolysis occurred, which could be the main mechanism of B‐cell adaptation. Thus, B cells have a powerful mechanism to adapt to the entry of HIV‐1 Tat, the efficiency of which may determine the frequency of lymphomagenesis in HIV‐1‐infected patients.

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Transactivator of Transcription (Tat)-Induced Neuroinflammation as a Key Pathway in Neuronal Dysfunction: A Scoping Review

Muvenda,

Williams,

Williams

2024

Mol Neurobiol

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The activity of HIV-1 and its viral proteins within the central nervous system (CNS) is responsible for a wide array of neuropathological effects, resulting in a spectrum of neurocognitive deficits defined as HIV-associated neurocognitive disorders (HAND). Amongst the various viral proteins, the transactivator of transcription (Tat) remains detectable even with effective antiretroviral therapy (ART) and suppressed viremia, highlighting the significance of this protein in the modern ART era. Tat has been extensively researched in both fundamental and clinical settings due to its role in neuroinflammation, neuronal damage, and neurocognitive impairment amongst people living with HIV (PLHIV). To date, numerous fundamental studies have explored Tat-induced neuroinflammation. However, there is no clear consensus on the most frequently studied inflammatory markers or the consistency in the levels of these Tat-induced inflammatory marker levels across different studies. Therefore, we conducted a scoping review of studies investigating Tat-induced neuroinflammation. We conducted searches in PubMed, Scopus, and Web of Science databases using a search protocol tailored specifically to adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews (PRISMA-ScR) guidelines. From the 22 included studies, findings suggest that the HIV-1 Tat protein amplifies levels of neuroinflammatory markers. Amongst the vast array of inflammatory markers explored in the included studies, consistent results point to higher levels of CCL2, IL-6, IL-8, and TNF-α in primary cells and cell lines exposed to or transfected with HIV-1 Tat. These markers are regulated by key inflammatory pathways, such as the extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, the p38 MAPK pathway, and nuclear factor-kB (NF-kB). Furthermore, Tat has been shown to induce neuronal apoptosis, both directly and indirectly. With regards to study designs, utilizing full-length Tat101 at concentrations ranging from 100 to 1000 ng/ml and durations of 24 and 48 h appears optimal for investigating Tat-induced neuroinflammation. In this context, we highlight specific inflammatory markers and pathways that are potentially pivotal in Tat-induced neuroinflammation and subsequent neuronal damage. A deeper investigation into these markers and pathways is crucial to better understand their roles in the development of HAND.

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Human immunodeficiency virus-1 Tat exerts its neurotoxic effects by downregulating Sonic hedgehog signaling

Cited by 6 publications

References 36 publications

Integrated Analysis of the miRNA-mRNA Regulatory Network Involved in HIV-Associated Neurocognitive Disorder

Integrated Analysis of the miRNA-mRNA Regulatory Network Involved in HIV-Associated Neurocognitive Disorder

Compensatory reactions of B cells in response to chronic HIV‐1 Tat exposure

Transactivator of Transcription (Tat)-Induced Neuroinflammation as a Key Pathway in Neuronal Dysfunction: A Scoping Review

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