scholarly journals IFN-independent G0 arrest and SAMHD1 activation following TLR4 activation in macrophages

2019 ◽  
Author(s):  
P. Mlcochova ◽  
H. Winstone ◽  
L. Zuliani-Alvarez ◽  
R.K. Gupta
Keyword(s):  
Cell Cycle ◽  
Human Macrophages ◽  
E Coli ◽  
Molecular Pattern ◽  
Cell Arrest ◽  
Tlr4 Activation ◽  
Lps Activation ◽  
Sirna Knockdown ◽  
Cycle Regulation ◽  
Hiv 1

AbstractMonocyte-derived macrophages mostly reside in a resting, G0 state, expressing high levels of dephosphorylated, active SAMHD1. We have previously shown that macrophages can re-enter the cell cycle without division, into a G1-like state. This cell cycle re-entry is accompanied by phosphorylation of the dNTP hydrolase/ antiviral restriction factor SAMHD1 at T592 by the cyclin-dependent kinase CDK1. HIV-1 successfully infects macrophages in G1 through exploiting this naturally occurring window of opportunity where SAMHD1 antiviral activity is de-activated.Here we demonstrate for the first time that LPS activation of the pathogen associated molecular pattern (PAMP) receptor TLR4 induces G0 arrest in human macrophages. We show this G0 arrest is MyD88-independent and therefore NFkB independent. Furthermore, the effect of TLR4 activation on cell cycle is regulated by (a) the canonical IFN-dependent pathway following TBK1 activation and IRF3 translocation and (b) an IFN-independent pathway that occurs prior to TBK1 activation, and that is accompanied by CDK1 downregulation, p21 upregulation and SAMHD1 dephosphorylation at T592. Furthermore, we show by siRNA knockdown of SAMHD1 that the interferon independent pathway activated by TLR4 is able to potently block HIV-1 infection in macrophages specifically via SAMHD1. Finally, ingestion of whole E. Coli and TLR4 activation by macrophages also activates SAMHD1 via the interferon independent pathway.Together, these data demonstrate that macrophages can rapidly activate an intrinsic cell arrest and anti-viral state by activation of TLR4 prior to IFN secretion, thereby highlighting the importance of cell cycle regulation as a response to danger signals in human macrophages. Interferon independent activation of SAMHD1 by TLR4 represents a novel mechanism for limiting the HIV-1 reservoir size and should be considered for host-directed therapeutic approaches that may contribute to curative interventions.

TAMI-50. PATHWAYS ACTIVATION IN GL261 MICE GLIOMA CELLS BY HIV-1 GLYCOPROTEIN GP120

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi208-vi208
Author(s):  
Gabriel Valentín Guillama ◽  
Lilia Kucheryavykh
Keyword(s):  
Cell Cycle ◽  
Western Blot ◽  
Cell Cycle Regulation ◽  
Glycogen Synthase ◽  
Glioma Cells ◽  
Treatment Resistance ◽  
Signaling Mechanism ◽  
Knock Out ◽  
Cycle Regulation ◽  
Hiv 1

Abstract Patients infected with human immunodeficiency virus type 1 (HIV-1) are more prone to developing cancers, including glioblastomas (GBMs). The median survival for GBM patients with HIV is significantly shorter than for HIV-negative GBM patients, even though they receive the same treatments. This difference indicates that HIV infection is associated with more aggressive tumor behavior and with treatment resistance. Earlier we demonstrated that gp120, a main glycoprotein in the HIV shell, stimulates glycolysis and protein synthesis in glioma cells. The purpose of this study was to evaluate the underlying gp120 dependent signaling mechanism in glioma cell. Mouse glioma cells GL-261 were continuously cultured for 7 days in medium with and without soluble gp120 Bal III (100ng/ml) and collected for Western blot and Cell cycle assays. Western blot analysis presented an increase in phosphorylation of Proline-rich tyrosine kinase (Pyk2(Y402)), p38(YT100/Y182) and p70s6(T421/S424), the key proteins of the Pyk2 pathway, along with the increased levels of Akt(S473) and Glycogen Synthase Kinase 3b (GSK3b (S9)) phosphorylation. Flow cytometry analysis of Cell Cycle revealed an increase of G2/M phase in cells cultured in gp120 Bal III when compared to control cells. Furthermore, GL-261 cells with knock-out of Pyk2 via CRISPR Cas 9 gene editing showed no significant change in cell cycle regulation when cultured with gp120 Bal III.Overall, these results demonstrate that gp120 triggers activation of Pyk2/MAPK and Akt/GSK3b pathways and alter cell cycle regulation in GBM. This research was made possible by NIH grant number 1SC1GM122691.

scholarly journals Cell Cycle Regulation in Macrophages and Susceptibility to HIV-1

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 839
Author(s):  
Isabella A. T. M. Ferreira ◽  
J. Zachary Porterfield ◽  
Ravindra K. Gupta ◽  
Petra Mlcochova
Keyword(s):  
Cell Cycle ◽  
Environmental Changes ◽  
Macrophage Cell ◽  
First Line ◽  
Important Target ◽  
Cell Cycle Transition ◽  
And Function ◽  
Cycle Regulation ◽  
Hiv 1 ◽  
Deoxynucleotide Triphosphate

Macrophages are the first line of defence against invading pathogens. They play a crucial role in immunity but also in regeneration and homeostasis. Their remarkable plasticity in their phenotypes and function provides them with the ability to quickly respond to environmental changes and infection. Recent work shows that macrophages undergo cell cycle transition from a G0/terminally differentiated state to a G1 state. This G0-to-G1 transition presents a window of opportunity for HIV-1 infection. Macrophages are an important target for HIV-1 but express high levels of the deoxynucleotide-triphosphate hydrolase SAMHD1, which restricts viral DNA synthesis by decreasing levels of dNTPs. While the G0 state is non-permissive to HIV-1 infection, a G1 state is very permissive to HIV-1 infection. This is because macrophages in a G1 state switch off the antiviral restriction factor SAMHD1 by phosphorylation, thereby allowing productive HIV-1 infection. Here, we explore the macrophage cell cycle and the interplay between its regulation and permissivity to HIV-1 infection.

scholarly journals HIV-1 gp120 and morphine induced oxidative stress: role in cell cycle regulation

2015 ◽  
Vol 6 ◽  
Author(s):  
Thangavel Samikkannu ◽  
Deepa Ranjith ◽  
Kurapati V. K. Rao ◽  
Venkata S. R. Atluri ◽  
Emely Pimentel ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Cycle Regulation ◽  
Hiv 1

scholarly journals Genetic association of G2/M checkpoint genes with susceptibility to HIV-1 infection and AIDS progression in northern Chinese MSM population

2020 ◽  
Author(s):  
Jiawei Wu ◽  
Xuelong Zhang ◽  
Kaili Wang ◽  
Lidan Xu ◽  
Bangquan Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Genetic Variants ◽  
Cell Cycle Regulation ◽  
Northern China ◽  
Aids Progression ◽  
Northern Chinese ◽  
Key Genes ◽  
Cycle Regulation ◽  
Checkpoint Genes ◽  
Hiv 1

Abstract Background MSM has a high risk of HIV infection. Previous studies showed that the cell cycle regulation played an important role in HIV-1 infection, especially in G2/M checkpoint. The ATR, Chk1, Cdc25C and CDK1 are key genes in G2/M checkpoint. However, the association between the SNPs of these genes and susceptibility to HIV-1 infection and AIDS progression remains unknown. Results 42 tSNPs of G2/M checkpoint genes were genotyped to analyze the association between these tSNPs and susceptibility to HIV-1 infection and AIDS progression among MSM (529 HIV − 1 seropositive men and 529 HIV-1 seronegative men) in northern China. The results showed that rs34660854-A and rs75368165-A in ATR gene and rs3756766-A in Cdc25C gene could increase the risk of HIV-1 infection (P = 0.049, P = 0.020 and P = 0.010, respectively), and ATR rs75069062 and Chk1 rs10893405 were significantly associated with AIDS progression (P = 0.026 and P = 0.029, respectively). Besides, rs34660854 and rs75368165 in ATR gene, rs12576279 and rs540436 in Chk1 gene, rs3756766 in Cdc25C gene and rs139245206 in CDK1 gene were significantly associated with HIV-1 infection under different models (P < 0.05). Conclusions The genetic variants of G2/M checkpoint genes had a molecular impact on the genesis of HIV-1 infection and AIDS progression in northern Chinese MSM population.

Biological Role of CDK 11 and 12 in Cell Cycle and its Function in Tumorigenesis

2020 ◽  
Author(s):  
Shamim Mushtaq
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Web Of Science ◽  
The Body ◽  
Main Role ◽  
Hallmarks Of Cancer ◽  
Cyclin Dependent Kinases ◽  
Tumor Studies ◽  
Cycle Regulation

Uninhibited proliferation and abnormal cell cycle regulation are the hallmarks of cancer. The main role of cyclin dependent kinases is to regulate the cell cycle and cell proliferation. These protein kinases are frequently down regulated or up regulated in various cancers. Two CDK family members, CDK 11 and 12, have contradicting views about their roles in different cancers. For example, one study suggests that the CDK 11 isoforms, p58, inhibits growth of breast cancer whereas, the CDK 11 isoform, p110, is highly expressed in breast tumor. Studies regarding CDK 12 show variation of opinion towards different parts of the body, however there is a consensus that upregulation of cdk12 increases the risk of breast cancer. Hence, CDK 11 and CDK 12 need to be analyzed to confirm their mechanism and their role regarding therapeutics, prognostic value, and ethnicity in cancer. This article gives an outline on both CDKs of information known up to date from Medline, PubMed, Google Scholar and Web of Science search engines, which were explored and thirty relevant researches were finalized.

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