The involvement of microRNAs in HCV and HIV infection

Joshi, Nicky; Tak, Madhuri Chandane; Mukherjee, Anupam

doi:10.1177/25151355221106104

Cited by 6 publications

(6 citation statements)

References 116 publications

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“…HIV encodes at least four v-miRNAs (64). These have been shown to be involved in regulating viral replication, cell survival, host gene expression, and latency (45, 65, 66). However, the expression of these v-miRNAs are controversial (64).…”

Section: Discussionmentioning

confidence: 99%

“…It is intriguing that deletion of multiple genes involved in either the maturation (Drosha, Dicer or XPO5) or function of miRNAs (Ago2) caused both an increase in susceptibility to 6mer seed toxicity as well as an increase in HIV infection. Some c-miRNAs have been shown to have antiviral activities (reviewed in (66)) and that would suggest a higher expression of HIV in cells lacking miRNA biogenesis enzymes or Ago2. However, this has never been described to affect the core virus before reverse transcription.…”

Section: Discussionmentioning

confidence: 99%

“…It is therefore not to be expected that even eliminating all RISC activity would completely block HIV induced cytotoxicity. Some c-miRNAs have been shown to have antiviral activities (reviewed in (66)) and that would suggest a higher expression of HIV in cells lacking miRNA biogenesis enzymes or Ago2. We did detect a higher expression of HIV in all mutant cells (data not shown) and this could be due to altered miRNA levels/activity affecting expression levels of the HIV entry receptors.…”

Section: Discussionmentioning

confidence: 99%

“…However, the expression of these v-miRNAs are controversial (64). In addition, the expression of a number of c-miRNAs is affected by the virus and some have anti-viral activities (reviewed in (66)). Of the v-miRNAs, the only v-miRNA we detected in the RISC of infected cells in significant numbers was miR-TAR-3p.…”

Section: Discussionmentioning

confidence: 99%

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Contribution of 6mer seed toxicity to HIV-1 induced cytopathicity

Vaidyanathan

Taylor

Hope

et al. 2022

Preprint

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HIV-1 (HIV) infects CD4 positive T cells, the gradual depletion of which can lead to the onset of Acquired Immunodeficiency Syndrome (AIDS) in the absence of antiretroviral therapy (ART). Several forms of cell death have been shown to be involved in HIV-mediated killing of either directly infected or bystander cells. It is still unknown, however, why some cells survive HIV infection and persist as part of the latently infected reservoir that reliably causes recurrent viremia upon ART cessation. Improved understanding of the mechanisms of HIV-mediated cell death could inform innovations designed to clear the latent reservoir. Death Induced by Survival gene Elimination (DISE) is an RNA interference (RNAi)-based mechanism that kills cells through short (s)RNAs with toxic 6mer seeds (pos. 2-7 of sRNA). These toxic seeds target reverse complementary seed matches in the 3'UTR of mRNA transcripts to decrease expression of hundreds of genes that are critical for cell survival. In most cells under normal conditions, highly expressed cell-encoded non-toxic microRNAs (miRNAs) block access of toxic sRNAs to the RNA-induced silencing complex (RISC) that mediates RNAi, promoting cell survival. We now report that infection of cells with HIV results in RISC-loading of an HIV-encoded miRNA, v-miRNA HIV-miR-TAR-3p, which kills cells by DISE through a noncanonical (pos. 3-8) 6mer seed. In addition, cellular RISC bound sRNAs shift to lower seed viability. Both these effects also occur with latent HIV provirus reactivation in J-Lat cells, a well-established cell model of HIV latency. Cells lacking expression of miRNA biogenesis genes Drosha, Dicer and Exportin 5 cannot produce protective miRNAs and therefore do not block RISC loading of the v-miRNA HIV-miR-TAR-3p. These mutant cells, as well as cells lacking expression of the RISC component Ago2, are hypersensitive to cell death via DISE induced by HIV infection. More precise targeting of the balance between protective and cytotoxic miRNAs could specifically and transiently increase silencing of cell survival genes to increase DISE. This could be a new addition to a ″shock and kill″ strategy to enhance depletion of the provirus reservoir during suppressive ART.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Contribution of 6mer seed toxicity to HIV-1 induced cytopathicity

Vaidyanathan

Taylor

Hope

et al. 2022

Preprint

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“…Increasing evidence demonstrates that miRNAs are one of the central factors in the interaction network between virus and host. However, the expression of miRNAs for disease treatment has so far been a difficult task due to their variable nature in different situations [ 6 ], but the same nature of being differentially expressed under different conditions allows miRNAs to be used as biomarkers for diseases. Some special miRNAs are highly correlated with the progression of liver-specific pathologies, and altered levels of miRNAs are even more sensitive and specific than those of conventional proteins.…”

Section: Introductionmentioning

confidence: 99%

A Mixture Method for Robust Detection HCV Early Diagnosis Biomarker with ML Approach and Molecular Docking

Gholizadeh

Łapczuk-Romańska

Post

et al. 2023

IJMS

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Given the substantial correlation between early diagnosis and prolonged patient survival in HCV patients, it is vital to identify a reliable and accessible biomarker. The purpose of this research was to identify accurate miRNA biomarkers to aid in the early diagnosis of HCV and to identify key target genes for anti-hepatic fibrosis therapeutics. The expression of 188 miRNAs in 42 HCV liver patients with different functional states and 23 normal livers were determined using RT-qPCR. After screening out differentially expressed miRNA (DEmiRNAs), the target genes were predicted. To validate target genes, an HCV microarray dataset was subjected to five machine learning algorithms (Random Forest, Adaboost, Bagging, Boosting, XGBoost) and then, based on the best model, importance features were selected. After identification of hub target genes, to evaluate the potency of compounds that might hit key hub target genes, molecular docking was performed. According to our data, eight DEmiRNAs are associated with early stage and eight DEmiRNAs are linked to a deterioration in liver function and an increase in HCV severity. In the validation phase of target genes, model evaluation revealed that XGBoost (AUC = 0.978) outperformed the other machine learning algorithms. The results of the maximal clique centrality algorithm determined that CDK1 is a hub target gene, which can be hinted at by hsa-miR-335, hsa-miR-140, hsa-miR-152, and hsa-miR-195. Because viral proteins boost CDK1 activation for cell mitosis, pharmacological inhibition may have anti-HCV therapeutic promise. The strong affinity binding of paeoniflorin (−6.32 kcal/mol) and diosmin (−6.01 kcal/mol) with CDK1 was demonstrated by molecular docking, which may result in attractive anti-HCV compounds. The findings of this study may provide significant evidence, in the context of the miRNA biomarkers, for early-stage HCV diagnosis. In addition, recognized hub target genes and small molecules with high binding affinity may constitute a novel set of therapeutic targets for HCV.

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