Inhibition of miR-155 Promotes TGF-β Mediated Suppression of HIV Release in the Cervical Epithelial Cells

Gokavi, Jyotsna; Sadawarte, Sharwari; Shelke, Anant; Kulkarni‐Kale, Urmila; Thakar, Madhuri; Saxena, Vandana

doi:10.3390/v13112266

Cited by 7 publications

(7 citation statements)

References 70 publications

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“…These findings thus suggest that miR-155 has the potential to regulate the expression of host restriction factors. Similar findings were previously reported by our group, where we showed that miR-155 inhibition increased the expression of APOBEC-3G, IFI-16 and IFITM-3 in cervical epithelial cells [127]. The host restriction factors are the type-1 interferon-induced specialized host proteins that inhibit virus replication at multiple stages [112,[128][129][130] and influence the course of HIV infection and disease outcome [131,132].…”

Section: Discussionsupporting

confidence: 89%

MiR-155 Negatively Regulates Anti-Viral Innate Responses among HIV-Infected Progressors

Pawar,

Gokavi,

Wakhare

et al. 2023

Viruses

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HIV infection impairs host immunity, leading to progressive disease. An anti-retroviral treatment efficiently controls viremia but cannot completely restore the immune dysfunction in HIV-infected individuals. Both host and viral factors determine the rate of disease progression. Among the host factors, innate immunity plays a critical role; however, the mechanism(s) associated with dysfunctional innate responses are poorly understood among HIV disease progressors, which was investigated here. The gene expression profiles of TLRs and innate cytokines in HIV-infected (LTNPs and progressors) and HIV-uninfected individuals were examined. Since the progressors showed a dysregulated TLR-mediated innate response, we investigated the role of TLR agonists in restoring the innate functions of the progressors. The stimulation of PBMCs with TLR3 agonist-poly:(I:C), TLR7 agonist-GS-9620 and TLR9 agonist-ODN 2216 resulted in an increased expression of IFN-α, IFN-β and IL-6. Interestingly, the expression of IFITM3, BST-2, IFITM-3, IFI-16 was also increased upon stimulation with TLR3 and TLR7 agonists, respectively. To further understand the molecular mechanism involved, the role of miR-155 was explored. Increased miR-155 expression was noted among the progressors. MiR-155 inhibition upregulated the expression of TLR3, NF-κB, IRF-3, TNF-α and the APOBEC-3G, IFITM-3, IFI-16 and BST-2 genes in the PBMCs of the progressors. To conclude, miR-155 negatively regulates TLR-mediated cytokines as wel l as the expression of host restriction factors, which play an important role in mounting anti-HIV responses; hence, targeting miR-155 might be helpful in devising strategic approaches towards alleviating HIV disease progression.

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Section: Discussionsupporting

confidence: 89%

MiR-155 Negatively Regulates Anti-Viral Innate Responses among HIV-Infected Progressors

Pawar,

Gokavi,

Wakhare

et al. 2023

Viruses

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“…In a prior investigation, a similar expression pattern of miR-182, miR-200c and miR-125b was observed in the serum of HIV-positive women [6]. In contrast, previous research has reported upregulated miR-182 and downregulated miR-146a in HIV-uninfected patients with sepsis, demonstrating signi cant lymphopenia and depleted CD4 and CD8 T-cells [7]. This suggests that the downregulation of miR-182 is HIV-dependent.…”

Section: Discussionmentioning

confidence: 72%

“…The ndings have signi cant implications for understanding the molecular mechanisms underlying cervical cancer risk. Since an earlier study demonstrated that miR-143, miR-145, miR-146a and miR-182 play direct roles in immunological processes [7], this study evaluates the potential utility of these miRNAs as predictive biomarkers for cervical cancer risk assessment and their suitability as therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

Molecular Signatures of Cervical Cancer Risk in the Context of HIV Infection: Potential biomarkers of immune activation

Okoye

2023

Preprint

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The disparity in cervical cancer incidence and mortality between high-income and low-income countries, exacerbated by the co-occurrence of HIV infection and cervical cancer, presents a complex and distinctive healthcare challenge. Addressing this challenge necessitates a comprehensive investigation into intricate molecular markers for predicting heightened cancer risk. This study assessed the cellular levels of cervical cancer-related specific oncomirs (miR-21, miR-146a, miR-155, miR-182, and miR-200c) and tumour suppressors (miR-let-7b, miR-125b, miR-143, miR-145, and p53) among women living with HIV (HIV+) and those without HIV (HIV-). Methods: This case-control study was conducted from May 2017 to April 2019 in Abeokuta, Nigeria, and involved two groups: HIV+ (n = 103) and HIV- women (n = 70). Results: The study revealed significantly higher levels of miR-155 and p53 in HIV+ women compared to their HIV- counterparts (p = 0.046 and 0.033, respectively). Conversely, significantly lower levels of miR-182, miR-200c, and miR-125b were observed in HIV+ women compared to their HIV- counterparts (p= 0.035, 0.045 and 0.004, respectively). Notably, a significant positive correlation was observed between miR-155 and miR-145 in both HIV+ and HIV- women (p < 0.05). Among HIV- women, direct relationships were also observed between miR-155 and miR-125b (p= 0.004), miR-200c and miR-125b (p= 0.033), and miR-200c and p53 (p= 0.003). Conclusion: This study indicates that HIV upregulates p53 and miR-155, and downregulates miR-125b, miR-182, and miR-200c. This suggests that the upregulation of the tri-miRNA and downregulation of miR-155 through targeted therapy could mitigate HIV-associated immune activation thereby forestalling cervical cancer development.

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“…Cervical epithelial cells are widely believed to support internalizing, transcytosing, and transinfecting CD4-positive cells with HIV-1 [20,21]. The majority of reports indicate that this process takes place without infection of the epithelial cells, the recent reports emphasize that these cells are also susceptible to productive infection with HIV-1 [22][23][24]. The most current reports indicated that bronchial, renal, and gastric epithelial cells could also produce infectious retroviruses as a result of viral transcription and integration [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Lactate Suppresses Retroviral Transduction in Cervical Epithelial Cells through DNA-PKcs Modulation

Wagner

Sobierajska

Kania

et al. 2021

IJMS

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Recently, we have shown the molecular basis for lactate sensing by cervical epithelial cells resulting in enhanced DNA repair processes through DNA-PKcs regulation. Interestingly, DNA-PKcs is indispensable for proper retroviral DNA integration in the cell host genome. According to recent findings, the mucosal epithelium can be efficiently transduced by retroviruses and play a pivotal role in regulating viral release by cervical epithelial cells. This study examined the effects of lactate on lentiviral transduction in cervical cancer cells (HeLa, CaSki, and C33A) and model glioma cell lines (DNA-PKcs proficient and deficient). Our study showed that L- and D-lactate enhanced DNA-PKcs presence in nuclear compartments by between 38 and 63%, which corresponded with decreased lentiviral transduction rates by between 15 and 36%. Changes in DNA-PKcs expression or its inhibition with NU7441 also greatly affected lentiviral transduction efficacy. The stimulation of cells with either HCA1 agonist 3,5-DHBA or HDAC inhibitor sodium butyrate mimicked, in part, the effects of L-lactate. The inhibition of lactate flux by BAY-8002 enhanced DNA-PKcs nuclear localization which translated into diminished lentiviral transduction efficacy. Our study suggests that L- and D-lactate present in the uterine cervix may play a role in the mitigation of viral integration in cervical epithelium and, thus, restrict the viral oncogenic and/or cytopathic potential.

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Inhibition of miR-155 Promotes TGF-β Mediated Suppression of HIV Release in the Cervical Epithelial Cells

Cited by 7 publications

References 70 publications

MiR-155 Negatively Regulates Anti-Viral Innate Responses among HIV-Infected Progressors

MiR-155 Negatively Regulates Anti-Viral Innate Responses among HIV-Infected Progressors

Molecular Signatures of Cervical Cancer Risk in the Context of HIV Infection: Potential biomarkers of immune activation

Lactate Suppresses Retroviral Transduction in Cervical Epithelial Cells through DNA-PKcs Modulation

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