Gene Co-Expression Network Modular Analysis Reveals Altered Immune Mechanisms in HIV-HAND

Petralia, Maria Cristina; Nicoletti, Ferdinando; Tancheva, Lyubka; Kalfin, Reni; Fagone, Paolo; Mangano, Katia

doi:10.3390/brainsci12101378

Cited by 3 publications

(5 citation statements)

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“…TMBIM5-knockout cells are more sensitive to apoptosis elicited by staurosporine or BH3 mimetic inhibitors of Bcl-2 and Bcl-xL [ 225 , 226 ]. Interestingly, global gene expression data show that TMBIM5 transcript levels are down-regulated in infected monocytes and increased in astrocytes of HIV-1 HAND patients [ 214 , 215 ]. Given the limited data available, further investigations are needed to determine whether TMBIM5 plays a role in the induction of apoptosis downstream of ATF4 in response to HIV-1 infection.…”

Section: Atf4 Role During Hiv-1 Replicationmentioning

confidence: 99%

ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor

Corne,

Adolphe,

Estaquier

et al. 2024

Biology

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Cellular integrated stress response (ISR), the mitochondrial unfolded protein response (UPRmt), and IFN signaling are associated with viral infections. Activating transcription factor 4 (ATF4) plays a pivotal role in these pathways and controls the expression of many genes involved in redox processes, amino acid metabolism, protein misfolding, autophagy, and apoptosis. The precise role of ATF4 during viral infection is unclear and depends on cell hosts, viral agents, and models. Furthermore, ATF4 signaling can be hijacked by pathogens to favor viral infection and replication. In this review, we summarize the ATF4-mediated signaling pathways in response to viral infections, focusing on human immunodeficiency virus 1 (HIV-1). We examine the consequences of ATF4 activation for HIV-1 replication and reactivation. The role of ATF4 in autophagy and apoptosis is explored as in the context of HIV-1 infection programmed cell deaths contribute to the depletion of CD4 T cells. Furthermore, ATF4 can also participate in the establishment of innate and adaptive immunity that is essential for the host to control viral infections. We finally discuss the putative role of the ATF4 paralogue, named ATF5, in HIV-1 infection. This review underlines the role of ATF4 at the crossroads of multiple processes reflecting host–pathogen interactions.

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Section: Atf4 Role During Hiv-1 Replicationmentioning

confidence: 99%

ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor

Corne,

Adolphe,

Estaquier

et al. 2024

Biology

View full text Add to dashboard Cite

show abstract

“…TMBIM5knockout cells are more sensitive to apoptosis elicited by staurosporine or BH3 mimetic inhibitors of Bcl-2 and Bcl-xL [225,226]. Interestingly, global gene expression data show that TMBIM5 transcript levels are down-regulated in infected monocytes and increased in astrocytes of HIV-1 HAND patients [214,215]. Given the limited data available, further investigations are needed to determine whether TMBIM5 plays a role in the induction of apoptosis downstream of ATF4 in response to HIV-1 infection.…”

Section: Tp53bp2/aspp2mentioning

confidence: 99%

ATF4 Signaling in HIV Infection: Viral Subversion of a Stress Response Transcription Factor

Corne,

Adolphe,

Estaquier

et al. 2024

Preprint

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Cellular Integrated Stress Response (ISR), the mitochondrial Unfolded Protein Response (UP-Rmt) and the IFN signaling are associated with viral infections. The Activating transcription fac-tor 4 (ATF4) plays a pivotal role in these pathways and controls the expression of many genes involved in redox processes, amino acid metabolism, protein misfolding, autophagy and apop-tosis. The precise role of ATF4 during viral infection is unclear and depends on cell hosts, viral agents and models. Furthermore, ATF4 signaling can be hijacked by pathogens to favor viral in-fection and replication. In this review, we summarize the ATF4-mediated signaling pathways in response to viral infections, focusing on human immunodeficiency virus (HIV). We examine the consequences of ATF4 activation for HIV replication and reactivation. The role of ATF4 in au-tophagy and apoptosis is explored as in the context of HIV infection programmed cell deaths contribute to the depletion of CD4 T cells. Furthermore, ATF4 can also participate in the estab-lishment of innate and adaptive immunity that are essential for the host to control viral infec-tions. We finally discuss the putative role of the ATF4 paralogue, named ATF5, in HIV infection. This review underlines the role of ATF4 at the crossroads of multiple processes reflecting host-pathogen interactions.

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“…Control (18), HIV w/o NCI (18), HIV w/dementia w/o HIVE (21), HIV w/NCI and HIVE (15) Control ( 74), Alzheimer's disease (87) Control ( 9), Parkinson's disease ( 16) Raw data were normalized using the Robust Multi-array Average (RMA) method from the "affy" package in Bioconductor using R version 4.3.1 for Windows (http://www. bioconductor.org (accessed 23 April 2023)).…”

Section: Conditionsmentioning

confidence: 99%

“…One of the strengths of WGCNA is its ability to capture the complex interplay among genes, which is often missed by traditional differential expression analyses that consider each gene independently [49]. This makes WGCNA particularly suitable for the study of complex brain diseases that cause neurocognitive impairment, which is likely to involve the dysregulation of interconnected networks of genes rather than individual genes [21,[50][51][52]. In the context of neurocognitive impairment, which refers to deficits in cognitive functions like language, memory, attention, and problem-solving due to underlying neurological abnormalities or dysfunction [53], Neurocognitive impairment is a hallmark of many brain disorders [53,54].…”

Section: Signature-based Approach For Drug Repurposingmentioning

confidence: 99%

“…Neuroinflammation is mediated by activated microglia and astrocytes. In both Alzheimer's and Parkinson's diseases, as well as in HAND, neuroinflammatory processes brought about by microbial infections contribute to neuronal damage contribute to neuronal damage [2,21]. Genes like APOE and HLA-DR in both AD and PDD have been implicated in modulating immune responses in the brain, providing another layer of genetic commonality [13].…”

Section: Introductionmentioning

confidence: 99%

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Navigating the Gene Co-Expression Network and Drug Repurposing Opportunities for Brain Disorders Associated with Neurocognitive Impairment

Manuel,

Tayo

2023

Brain Sciences

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Neurocognitive impairment refers to a spectrum of disorders characterized by a decline in cognitive functions such as memory, attention, and problem-solving, which are often linked to structural or functional abnormalities in the brain. While its exact etiology remains elusive, genetic factors play a pivotal role in disease onset and progression. This study aimed to identify highly correlated gene clusters (modules) and key hub genes shared across neurocognition-impairing diseases, including Alzheimer’s disease (AD), Parkinson’s disease with dementia (PDD), HIV-associated neurocognitive disorders (HAND), and glioma. Herein, the microarray datasets AD (GSE5281), HAND (GSE35864), glioma (GSE15824), and PD (GSE7621) were used to perform Weighted Gene Co-expression Network Analysis (WGCNA) to identify highly preserved modules across the studied brain diseases. Through gene set enrichment analysis, the shared modules were found to point towards processes including neuronal transcriptional dysregulation, neuroinflammation, protein aggregation, and mitochondrial dysfunction, hallmarks of many neurocognitive disorders. These modules were used in constructing protein-protein interaction networks to identify hub genes shared across the diseases of interest. These hub genes were found to play pivotal roles in processes including protein homeostasis, cell cycle regulation, energy metabolism, and signaling, all associated with brain and CNS diseases, and were explored for their drug repurposing experiments. Drug repurposing based on gene signatures highlighted drugs including Dorzolamide and Oxybuprocaine, which were found to modulate the expression of the hub genes in play and may have therapeutic implications in neurocognitive disorders. While both drugs have traditionally been used for other medical purposes, our study underscores the potential of a combined WGCNA and drug repurposing strategy for searching for new avenues in the simultaneous treatment of different diseases that have similarities in gene co-expression networks.

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Gene Co-Expression Network Modular Analysis Reveals Altered Immune Mechanisms in HIV-HAND

Cited by 3 publications

References 30 publications

ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor

ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor

ATF4 Signaling in HIV Infection: Viral Subversion of a Stress Response Transcription Factor

Navigating the Gene Co-Expression Network and Drug Repurposing Opportunities for Brain Disorders Associated with Neurocognitive Impairment

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