Rapamycin reduces CCR5 mRNA levels in macaques: potential applications in HIV-1 prevention and treatment

AIDS ◽  
2007 ◽  
Vol 21 (15) ◽  
pp. 2108-2110 ◽  
Author(s):  
Bruce L Gilliam ◽  
Alonso Heredia ◽  
Anthony DeVico ◽  
Nhut Le ◽  
Douty Bamba ◽  
...  
Keyword(s):  
Mrna Levels ◽  
Prevention And Treatment ◽  
Potential Applications ◽  
Hiv 1

scholarly journals Rho-kinase inhibitor hydroxyfasudil protects against HIV-1 Tat-induced dysfunction of tight junction and neprilysin/Aβ transfer receptor expression in mouse brain microvessels

2021 ◽  
Vol 476 (5) ◽  
pp. 2159-2170
Author(s):  
Qiangtang Chen ◽  
Yu Wu ◽  
Yachun Yu ◽  
Junxiang Wei ◽  
Wen Huang
Keyword(s):  
Tight Junction ◽  
Signaling Pathway ◽  
Mouse Brain ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Brain Microvessels ◽  
Rho Kinase Inhibitor ◽  
Hiv 1

AbstractHIV-1 transactivator protein (Tat) induces tight junction (TJ) dysfunction and amyloid-beta (Aβ) clearance dysfunction, contributing to the development and progression of HIV-1-associated neurocognitive disorder (HAND). The Rho/ROCK signaling pathway has protective effects on neurodegenerative disease. However, the underlying mechanisms of whether Rho/ROCK protects against HIV-1 Tat-caused dysfunction of TJ and neprilysin (NEP)/Aβ transfer receptor expression have not been elucidated. C57BL/6 mice were administered sterile saline (i.p., 100 μL) or Rho-kinase inhibitor hydroxyfasudil (HF) (i.p., 10 mg/kg) or HIV-1 Tat (i.v., 100 μg/kg) or HF 30 min before being exposed to HIV-1 Tat once a day for seven consecutive days. Evans Blue (EB) leakage was detected via spectrophotometer and brain slides in mouse brains. The protein and mRNA levels of zonula occludens-1 (ZO-1), occludin, NEP, receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP1) in mouse brain microvessels were, respectively, analyzed by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. Exposure of the mice to HIV-1 Tat increased the amount of EB leakage, EB fluorescence intensity, blood–brain barrier (BBB) permeability, as well as the RAGE protein and mRNA levels, and decreased the protein and mRNA levels of ZO-1, occludin, NEP, and LRP1 in mouse brain microvessels. However, these effects were weakened by Rho-kinase inhibitor HF. Taken together, these results provide information that the Rho/ROCK signaling pathway is involved in HIV-1 Tat-induced dysfunction of TJ and NEP/Aβ transfer receptor expression in the C57BL/6 mouse brain. These findings shed some light on potentiality of inhibiting Rho/Rock signaling pathway in handling HAND.

The balance between p53 isoforms modulates the efficiency of HIV-1 infection in macrophages

2021 ◽  
Author(s):  
Yann Breton ◽  
Corinne Barat ◽  
Michel J. Tremblay
Keyword(s):  
Virus Replication ◽  
Potential Role ◽  
Host Factors ◽  
Fine Tuning ◽  
Mrna Levels ◽  
Cellular Environment ◽  
P53 Isoforms ◽  
Antiviral Role ◽  
Hiv 1

Several host factors influence HIV-1 infection and replication. The p53-mediated antiviral role in monocytes-derived macrophages (MDMs) was previously highlighted. Indeed, an increase in p53 level results in a stronger restriction against HIV-1 early replication steps through SAMHD1 activity. In this study, we investigated the potential role of some p53 isoforms in HIV-1 infection. Transfection of isoform-specific siRNA induces distinctive effects on the virus life cycle. For example, in contrast to a siRNA targeting all isoforms, a knockdown of Δ133p53 transcripts reduces virus replication in MDMs that is correlated with a decrease in phosphorylated inactive SAMHD1. Combination of Δ133p53 knockdown and Nutlin-3, a pharmacological inhibitor of MDM2 that stabilizes p53, further reduces susceptibility of MDMs to HIV-1 infection, thus suggesting an inhibitory role of Δ133p53 towards p53 antiviral activity. In contrast, p53β knockdown in MDMs increases the viral production independently of SAMHD1. Moreover, experiments with a Nef-deficient virus show that this viral protein plays a protective role against the antiviral environment mediated by p53. Finally, HIV-1 infection affects the expression pattern of p53 isoforms by increasing p53β and p53γ mRNA levels while stabilizing the protein level of p53α and some isoforms from the p53β subclass. The balance between the various p53 isoforms is therefore an important factor in the overall susceptibility of macrophages to HIV-1 infection, fine-tuning the p53 response against HIV-1. This study brings a new understanding of the complex role of p53 in virus replication processes in myeloid cells. Importance As of today, HIV-1 is still considered as a global pandemic without a functional cure, partly because of the presence of stable viral reservoirs. Macrophages constitute one of these cell reservoirs, contributing to the viral persistence. Studies investigating the host factors involved in cell susceptibility to HIV-1 infection might lead to a better understanding of the reservoir formation and will eventually allow the development of an efficient cure. Our team previously showed the antiviral role of p53 in macrophages, which acts by compromising the early steps of HIV-1 replication. In this study, we demonstrate the involvement of p53 isoforms, which regulates p53 activity and define the cellular environment influencing viral replication. In addition, the results concerning the potential role of p53 in antiviral innate immunity could be transposed to other fields of virology and suggest that knowledge in oncology can be applied to HIV-1 research.

scholarly journals Prevalence and risk factors for HIV-1 infection in rural Kilimanjaro region of Tanzania: Implications for prevention and treatment

2007 ◽  
Vol 7 (1) ◽  
Author(s):  
Elia J Mmbaga ◽  
Akhtar Hussain ◽  
Germana H Leyna ◽  
Kagoma S Mnyika ◽  
Noel E Sam ◽  
...  
Keyword(s):  
Risk Factors ◽  
Kilimanjaro Region ◽  
Prevention And Treatment ◽  
Hiv 1

scholarly journals Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection

2016 ◽  
Vol 12 (3) ◽  
pp. e1005520 ◽  
Author(s):  
Kshitij Wagh ◽  
Tanmoy Bhattacharya ◽  
Carolyn Williamson ◽  
Alex Robles ◽  
Madeleine Bayne ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Prevention And Treatment ◽  
Clade C ◽  
Hiv 1

scholarly journals TRAF6 and TAK1 contribute to SAMHD1-mediated negative regulation of NF-κB signaling

2020 ◽  
Author(s):  
Constanza E. Espada ◽  
Corine St. Gelais ◽  
Serena Bonifati ◽  
Victoria V. Maksimova ◽  
Michael P. Cahill ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Transforming Growth Factor ◽  
Negative Regulation ◽  
Innate Immune ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Intracellular Dntp ◽  
Hiv 1

Sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) restricts HIV-1 replication by limiting the intracellular dNTP pool. SAMHD1 also suppresses the activation of NF-κB in response to viral infections and inflammatory stimuli. However, the mechanisms by which SAMHD1 negatively regulates this pathway remain unclear. Here we show that SAMHD1-mediated suppression of NF-κB activation is modulated by two key mediators of NF-κB signaling, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and transforming growth factor-ß-activated kinase-1 (TAK1). We compared NF-κB activation stimulated by interleukin (IL)-1ß in monocytic THP-1 control and SAMHD1 knockout (KO) cells with and without partial TRAF6 knockdown (KD), or in cells treated with TAK1 inhibitors. Relative to control cells, IL-1ß-treated SAMHD1 KO cells showed increased phosphorylation of the inhibitor of NF-κB (IκBα), an indication of pathway activation, and elevated levels of TNF-α mRNA. Moreover, SAMHD1 KO combined with TRAF6 KD or pharmacological TAK1 inhibition reduced IκBα phosphorylation and TNF-α mRNA to the level of control cells. SAMHD1 KO cells infected with single-cycle HIV-1 showed elevated infection and TNF-α mRNA levels compared to control cells, and the effects were significantly reduced by TRAF6 KD or TAK1 inhibition. We further demonstrated that overexpressed SAMHD1 inhibited TRAF6-stimulated NF-κB reporter activity in HEK293T cells in a dose-dependent manner. SAMHD1 contains a nuclear localization signal (NLS), but an NLS-defective SAMHD1 exhibited a suppressive effect similar to the wild-type protein. Our data suggest that the TRAF6-TAK1 axis contributes to SAMHD1-mediated suppression of NF-κB activation and HIV-1 infection. Importance Cells respond to pathogen infection by activating a complex innate immune signaling pathway, which culminates in the activation of transcription factors and secretion of a family of functionally and genetically related cytokines. However, excessive immune activation may cause tissue damage and detrimental effects on the host. Therefore, in order to maintain host homeostasis, the innate immune response is tightly regulated during viral infection. We have reported SAMHD1 as a novel negative regulator of the innate immune response. Here, we provide new insights into SAMHD1-mediated negative regulation of the NF-κB pathway at the TRAF6-TAK1 checkpoint. We show that SAMHD1 inhibits TAK1 activation and TRAF6 signaling in response to proinflammatory stimuli. Interestingly, TRAF6 knockdown in SAMHD1-deficient cells significantly inhibited HIV-1 infection and activation of NF-κB induced by virus infection. Our research reveals a new negative regulatory mechanism by which SAMHD1 participates in the maintenance of cellular homeostasis during HIV-1 infection and inflammation.

scholarly journals HIV-1 Tat Regulates Occludin and AβTransfer Receptor Expression in Brain Endothelial Cells via Rho/ROCK Signaling Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Yanlan Chen ◽  
Wen Huang ◽  
Wenlin Jiang ◽  
Xianghong Wu ◽  
Biao Ye ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Immunofluorescent Staining ◽  
Mrna Levels ◽  
Protein Levels ◽  
Density Lipoprotein Receptor ◽  
Hiv 1

HIV-1 transactivator protein (Tat) has been shown to play an important role in HIV-associated neurocognitive disorders. The aim of the present study was to evaluate the relationship between occludin and amyloid-beta (Aβ) transfer receptors in human cerebral microvascular endothelial cells (hCMEC/D3) in the context of HIV-1-related pathology. The protein expressions of occludin, receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP1) in hCMEC/D3 cells were examined using western blotting and immunofluorescent staining. The mRNA levels of occludin, RAGE, and LRP1 were measured using quantitative real-time polymerase chain reaction. HIV-1 Tat at 1 µg/mL and the Rho inhibitor hydroxyfasudil (HF) at 30 µmol/L, with 24 h exposure, had no significant effect on hCMEC/D3 cell viability. Treatment with HIV-1 Tat protein decreased mRNA and protein levels of occludin and LRP1 and upregulated the expression of RAGE; however, these effects were attenuated by HF. These data suggest that the Rho/ROCK signaling pathway is involved in HIV-1 Tat-mediated changes in occludin, RAGE, and LRP1 in hCMEC/D3 cells. HF may have a beneficial influence by protecting the integrity of the blood-brain barrier and the expression of Aβtransfer receptors.

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