scholarly journals Decreased myoblast differentiation in chronic binge alcohol-administered simian immunodeficiency virus-infected male macaques: role of decreased miR-206

2017 ◽  
Vol 313 (3) ◽  
pp. R240-R250 ◽  
Author(s):  
L. Simon ◽  
S. M. Ford ◽  
K. Song ◽  
P. Berner ◽  
C. Vande Stouwe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Simian Immunodeficiency Virus ◽  
Critical Role ◽  
Myoblast Differentiation ◽  
Differentiation Potential ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Underlying Mechanisms

Skeletal muscle stem cells play a critical role in regeneration of myofibers. We previously demonstrated that chronic binge alcohol (CBA) markedly attenuates myoblast differentiation potential and myogenic gene expression. Muscle-specific microRNAs (miRs) are implicated in regulation of myogenic genes. The aim of this study was to determine whether myoblasts isolated from asymptomatic CBA-administered simian immunodeficiency virus (SIV)-infected macaques treated with antiretroviral therapy (ART) showed similar impairments and, if so, to elucidate potential underlying mechanisms. Myoblasts were isolated from muscle at 11 mo after SIV infection from CBA/SIV macaques and from time-matched sucrose (SUC)-treated SIV-infected (SUC/SIV) animals and age-matched controls. Myoblast differentiation and myogenic gene expression were significantly decreased in myoblasts from SUC/SIV and CBA/SIV animals compared with controls. SIV and CBA decreased muscle-specific miR-206 in plasma and muscle and SIV decreased miR-206 expression in myoblasts, with no statistically significant changes in other muscle-specific miRs. These findings were associated with a significant increase in histone deacetylase 4 (HDAC4) and decrease in myogenic enhancer factor 2C (MEF2C) expression in CBA/SIV muscle. Transfection with miR-206 inhibitor decreased myotube differentiation, increased expression of HDAC4, and decreased MEF2C, suggesting a critical role of miR-206 in myogenesis. Moreover, HDAC4 was confirmed to be a direct miR-206 target. These results support a mechanistic role for decreased miR-206 in suppression of myoblast differentiation resulting from chronic alcohol and SIV infection. The parallel changes in skeletal muscle and circulating levels of miR-206 warrant studies to establish the possible use of plasma miR-206 as an indicator of impaired muscle function.

scholarly journals Epigenomic mechanisms of alcohol-induced impaired differentiation of skeletal muscle stem cells; role of Class IIA histone deacetylases

2019 ◽  
Vol 51 (9) ◽  
pp. 471-479 ◽  
Author(s):  
Katherine Adler ◽  
Patricia E. Molina ◽  
Liz Simon
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Histone Deacetylases ◽  
Rhesus Macaques ◽  
Myoblast Differentiation ◽  
Differentiation Potential ◽  
Myotube Formation ◽  
Immunodeficiency Virus ◽  
Fusion Index

Loss of functional metabolic muscle mass remains a strong and consistent predictor of mortality among people living with human immunodeficiency virus (PLWH). PLWH have a higher incidence of alcohol use disorder (AUD), and myopathy is a significant clinical comorbidity due to AUD. One mechanism of skeletal muscle (SKM) mass maintenance and repair is by differentiation and fusion of satellite cells (SCs) to existing myofibers. Previous studies demonstrated that chronic binge alcohol (CBA) administration decreases SC differentiation potential, myogenic gene expression, and miR-206 expression in simian immunodeficiency virus (SIV)-infected male rhesus macaques and that miR-206 targets the Class IIA histone deacetylase, HDAC4. The aim of this study was to determine whether alcohol-induced increases in Class IIA HDACs mediate the observed decrease in differentiation potential of SCs. Data show that CBA dysregulated HDAC gene expression in SKM and myoblasts of SIV-infected macaques. CBA and antiretroviral therapy increased HDAC activity in SKM and this was positively correlated with HDAC4 gene expression. In vitro ethanol (ETOH) treatment increased HDAC expression during differentiation and decreased differentiation potential of myoblasts. HDAC expression was negatively correlated with fusion index and myotube formation, indicators of differentiation potential. Treatment with a Class II HDAC inhibitor, TMP195, restored differentiation in ETOH-treated myoblasts. MEF2C expression at day 3 of differentiation was positively correlated with fusion index and myotube formation. These findings suggest that an alcohol-mediated increase in Class IIA HDAC expression contributes to decreased myoblast differentiation by downregulating MEF2C, a transcription factor critical for myogenesis.

scholarly journals Enhanced Intestinal TGF-β/SMAD-Dependent Signaling in Simian Immunodeficiency Virus Infected Rhesus Macaques

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 806
Author(s):  
Nongthombam Boby ◽  
Alyssa Ransom ◽  
Barcley T. Pace ◽  
Kelsey M. Williams ◽  
Christopher Mabee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Simian Immunodeficiency Virus ◽  
Transforming Growth Factor ◽  
Rhesus Macaques ◽  
Transforming Growth Factor Β ◽  
Immunodeficiency Virus ◽  
Cellular Source ◽  
Siv Infection ◽  
Β Receptor ◽  
Differentiation And Proliferation

Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-β production that attributes to its pathological manifestations remain unknown. Here, we have shown increased production of TGF-β in a majority of intestinal CD3−CD20−CD68+ cells from acute and chronically SIV infected rhesus macaques, which negatively correlated with the frequency of jejunum CD4+ T cells. No significant changes in intestinal TGF-β receptor II expression were observed but increased production of the pSMAD2/3 protein and SMAD3 gene expression in jejunum tissues that were accompanied by a downregulation of SMAD7 protein and gene expression. Enhanced TGF-β production by intestinal CD3−CD20−CD68+ cells and increased TGF-β/SMAD-dependent signaling might be due to a disruption of a negative feedback loop mediated by SMAD7. This suggests that SIV infection impacts the SMAD-dependent signaling pathway of TGF-β and provides a potential framework for further study to understand the role of viral factor(s) in modulating TGF-β production and downregulating SMAD7 expression in SIV. Regulation of mucosal TGF-β expression by therapeutic TGF-β blockers may help to create effective antiviral mucosal immune responses.

scholarly journals Sequential Evolution and Escape from Neutralization of Simian Immunodeficiency Virus SIVsmE660 Clones in Rhesus Macaques

2012 ◽  
Vol 86 (16) ◽  
pp. 8835-8847 ◽  
Author(s):  
Fan Wu ◽  
Ilnour Ourmanov ◽  
Takeo Kuwata ◽  
Robert Goeken ◽  
Charles R. Brown ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Lavage Fluid ◽  
Vaccine Protection ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Intravenous Inoculation

Simian immunodeficiency virus (SIV) infection of rhesus macaques has become an important surrogate model for evaluating HIV vaccine strategies. The extreme resistance to neutralizing antibody (NAb) of many commonly used strains, such as SIVmac251/239 and SIVsmE543-3, limits their potential relevance for evaluating the role of NAb in vaccine protection. In contrast, SIVsmE660 is an uncloned virus that appears to be more sensitive to neutralizing antibody. To evaluate the role of NAb in this model, we generated full-length neutralization-sensitive molecular clones of SIVsmE660 and evaluated two of these by intravenous inoculation of rhesus macaques. All animals became infected and maintained persistent viremia that was accompanied by a decline in memory CD4+T cells in blood and bronchoalveolar lavage fluid. High titers of autologous NAb developed by 4 weeks postinoculation but were not associated with control of viremia, and neutralization escape variants were detected concurrently with the generation of NAb. Neutralization escape was associated with substitutions and insertion/deletion polymorphisms in the V1 and V4 domains of envelope. Analysis of representative variants revealed that escape variants also induced NAbs within a few weeks of their appearance in plasma, in a pattern that is reminiscent of the escape of human immunodeficiency virus type 1 (HIV-1) isolates in humans. Although early variants maintained a neutralization-sensitive phenotype, viruses obtained later in infection were significantly less sensitive to neutralization than the parental viruses. These results indicate that NAbs exert selective pressure that drives the evolution of the SIV envelope and that this model will be useful for evaluating the role of NAb in vaccine-mediated protection.

scholarly journals Identification of a Subset of Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus Strains Able To Exploit an Alternative Coreceptor on Untransformed Human Brain and Lymphoid Cells

2003 ◽  
Vol 77 (11) ◽  
pp. 6138-6152 ◽  
Author(s):  
Samantha J. Willey ◽  
Jacqueline D. Reeves ◽  
Richard Hudson ◽  
Koichi Miyake ◽  
Nathalie Dejucq ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Simian Immunodeficiency Virus ◽  
Cell Lines ◽  
Chemokine Receptors ◽  
Adult Brain ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT The chemokine receptors CCR5 and CXCR4 are the major coreceptors for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). At least 12 other chemokine receptors or close relatives support infection by particular HIV and SIV strains on CD4+ transformed indicator cell lines in vitro. However, the role of these alternative coreceptors in vivo is presently thought to be insignificant. Infection of cell lines expressing high levels of recombinant CD4 and coreceptors thus does not provide a true indication of coreceptor use in vivo. We therefore tested primary untransformed cell cultures that lack CCR5 and CXCR4, including astrocytes and brain microvascular endothelial cells (BMVECs), for naturally expressed alternative coreceptors functional for HIV and SIV infection. An adenovirus vector (Ad-CD4) was used to express CD4 in CD4− astrocytes and thus confer efficient infection if a functional coreceptor is present. Using a large panel of viruses with well-defined coreceptor usage, we identified a subset of HIV and SIV strains able to infect two astrocyte cultures derived from adult brain tissue. Astrocyte infection was partially inhibited by several chemokines, indicating a role for the chemokine receptor family in the observed infection. BMVECs were weakly positive for CD4 but negative for CCR5 and CXCR4 and were susceptible to infection by the same subset of isolates that infected astrocytes. BMVEC infection was efficiently inhibited by the chemokine vMIP-I, implicating one of its receptors as an alternative coreceptor for HIV and SIV infection. Furthermore, we tested whether the HIV type 1 and type 2 strains identified were able to infect peripheral blood mononuclear cells (PBMCs) via an alternative coreceptor. Several strains replicated in Δ32/Δ32 CCR5 PBMCs with CXCR4 blocked by AMD3100. This AMD3100-resistant replication was also sensitive to vMIP-I inhibition. The nature and potential role of this alternative coreceptor(s) in HIV infection in vivo is discussed.

scholarly journals Critical Role of cRel Subunit of NF-κB in Sepsis Survival

2011 ◽  
Vol 79 (5) ◽  
pp. 1848-1854 ◽  
Author(s):  
Emilie Courtine ◽  
Frédéric Pène ◽  
Nicolas Cagnard ◽  
Julie Toubiana ◽  
Catherine Fitting ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Critical Role ◽  
Cecal Ligation ◽  
Gene Expression Profiles ◽  
Severe Infection ◽  
A Genome ◽  
Underlying Mechanisms ◽  
Pathogen Clearance

ABSTRACTNF-κB is a critical regulator of gene expression during severe infections. NF-κB comprises homo- and heterodimers of proteins from the Rel family. Among them, p50 and p65 have been clearly implicated in the pathophysiology of sepsis. In contrast, the role of cRel in sepsis is still controversial and has been poorly studied in single-pathogen infections. We aimed to investigate the consequences of cRel deficiency in a cecal ligation and puncture (CLP) model of sepsis. We have approached the underlying mechanisms of host defense by analyzing bacterial clearance, systemic inflammation, and the distribution of spleen dendritic cell subsets. Moreover, by using a genome-wide technology, we have also analyzed the CLP-induced modifications in gene expression profiles both in wild-type (wt) and inrel−/−mice. The absence of cRel enhances mortality due to polymicrobial sepsis. Despite normal pathogen clearance, cRel deficiency leads to an altered systemic inflammatory response associated with a sustained loss of the spleen lymphoid dendritic cells. Furthermore, a whole-blood microarray study reveals that the differential outcome between wt andrel−/−mice during sepsis is preceded by remarkable changes in the expression of hundreds of genes involved in aspects of host-pathogen interaction, such as host survival and lipid metabolism. In conclusion, cRel is a key NF-κB member required for host antimicrobial defenses and a regulatory transcription subunit that controls the inflammatory and immune responses in severe infection.

scholarly journals Inhibition of SIRT2 suppresses hepatic fibrosis

2016 ◽  
Vol 310 (11) ◽  
pp. G1155-G1168 ◽  
Author(s):  
Maribel Arteaga ◽  
Na Shang ◽  
Xianzhong Ding ◽  
Sherri Yong ◽  
Scott J. Cotler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Histone Deacetylases ◽  
Critical Role ◽  
Stellate Cells ◽  
Novel Strategy ◽  
Underlying Mechanisms

Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis.

scholarly journals Intrathecal Humoral Responses Are Inversely Associated with the Frequency of Simian Immunodeficiency Virus Macrophage-Tropic Variants in the Central Nervous System

2009 ◽  
Vol 83 (16) ◽  
pp. 8282-8288 ◽  
Author(s):  
Elena Ryzhova ◽  
Pyone Aye ◽  
Tom Harvey ◽  
Wei Cao ◽  
Andrew Lackner ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Simian Immunodeficiency Virus ◽  
Humoral Response ◽  
Temporal Course ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
The Central Nervous System ◽  
Humoral Responses

ABSTRACT Sustained simian immunodeficiency virus (SIV) infection of the central nervous system (CNS) depends on macrophage-tropic (M-tropic) strains that are often easily neutralizable. The CNS is often thought of as an immunologically privileged site that fosters replication of M-tropic quasispecies. Yet, there are limited data addressing the intrathecal antibody response or the role of the humoral response, in general, to control M-tropic strains. We investigated the temporal course of the intrathecal fusion inhibitory activity against an M-tropic viral variant and found an inverse relationship between the magnitude of this neutralization and the prevalence of M-tropic populations. These studies suggest a role for the humoral response in the suppression of M-tropic viral species in the CNS in experimental SIV infection.

scholarly journals Requirement for PINCH in Skeletal Myoblast Differentiation

2021 ◽  
Author(s):  
Siyi Xie ◽  
Chushan Fang ◽  
Yujie Gao ◽  
Jie Yan ◽  
Lina Luo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Skeletal Muscles ◽  
Molecular Mechanisms ◽  
Myogenic Differentiation ◽  
Critical Role ◽  
The Body ◽  
Myoblast Differentiation ◽  
Skeletal Myogenesis ◽  
Congenital Myopathies

Abstract Background: Skeletal muscle is composed of bundles of myofibers ensheathed by extracellular matrix networks. Malformation of skeletal muscle during embryonic development results in congenital myopathies. Disease mechanisms of congenital myopathies remain unclear. PINCH, an adaptor of focal adhesion complex, plays essential roles in multiple cellular processes and organogenesis. Elucidation of the molecular mechanisms underlying skeletal myogenesis will offer new insights into pathogenesis of myopathies.Methods: We generated muscle-specific PINCH knock-out mice to study the functional role of PINCH in skeletal myogenesis. Histologic and Transmission Electron Microscopy analysis demonstrated that Impaired myogenic differentiation and maturation in mice with PINCH1 being ablated in skeletal muscle progenitors, and Ablation of PINCH1 and PINCH2 resulted in reduced size of muscle fibers and impaired multinucleation; Cell culture and immunostaining showed that defects in myoblast fusion and cytoskeleton assembly in PINCH double mutant mice; Western blotting showed that defects in expression of cytoskeleton proteins and proteins involved in myogenesis in DMUT skeletal muscles.Results: Double ablation of PINCH1 and PINCH2 resulted in early postnatal lethality with reduced size of skeletal muscles and detachment of diaphragm muscles from the body wall. Myofibers of PINCH mutant myofibers failed to undergo multinucleation and exhibited disrupted sarcomere structures. The mutant myoblasts in culture were able to adhere to newly formed myotubes, but impeded in cell fusion and subsequent sarcomere genesis and cytoskeleton organization. Consistent with this, expression of integrin β1 and some cytoskeleton proteins, and phosphorylation of ERK and AKT were significantly reduced in PINCH mutants. Expression of MRF4, the most highly expressed myogenic factor at late stages of myogenesis, was abolished in PINCH mutants, that could contribute to observed phenotypes. In addition, mice with PINCH1 being ablated in myogenic progenitors exhibited only mild centronuclear myopathic changes, suggesting a compensatory role of PINCH2 in myogenic differentiation, indicating a critical role of PINCH proteins in myogenic differentiation.Conclusion: Our results demonstrated an essential role of PINCH in skeletal myogenic differentiation.

scholarly journals Identification and Simian Immunodeficiency Virus Infection of CD1d-Restricted Macaque Natural Killer T Cells

2003 ◽  
Vol 77 (14) ◽  
pp. 8153-8158 ◽  
Author(s):  
Alison Motsinger ◽  
Agnes Azimzadeh ◽  
Aleksandar K. Stanic ◽  
R. Paul Johnson ◽  
Luc Van Kaer ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Simian Immunodeficiency Virus ◽  
Cell Receptor ◽  
Nkt Cells ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Hiv 1 ◽  
Natural Killer T

ABSTRACT Natural killer T (NKT) cells express a highly conserved T-cell receptor (TCR) and recognize glycolipids in the context of CD1d molecules. We recently demonstrated that CD4+ NKT cells are highly susceptible to human immunodeficiency virus type 1 (HIV-1) infection and are selectively depleted in HIV-infected individuals. Here, we identified macaque NKT cells using CD1d tetramers and human Vα24 antibodies. Similar to human NKT cells, α-galactosylceramide (α-GalCer)-pulsed dendritic cells activate and expand macaque NKT cells. Upon restimulation with α-GalCer-pulsed CD1d+ cells, macaque NKT cells secreted high levels of cytokines, a characteristic of these T cells. Remarkably, the majority of resting and activated macaque NKT cells expressed CD8, and a smaller portion expressed CD4. Macaque NKT cells also expressed the HIV-1/simian immunodeficiency virus (SIV) coreceptor CCR5, and the CD4+ subset was susceptible to SIV infection. Identification of macaque NKT cells has major implications for delineating the role of these cells in nonhuman primate disease models of HIV as well as other pathological conditions, such as allograft rejection and autoimmunity.

scholarly journals Early Regeneration of Thymic Progenitors in Rhesus Macaques Infected with Simian Immunodeficiency Virus

1998 ◽  
Vol 187 (11) ◽  
pp. 1767-1778 ◽  
Author(s):  
Joanna J. Wykrzykowska ◽  
Michael Rosenzweig ◽  
Ronald S. Veazey ◽  
Meredith A. Simon ◽  
Katherine Halvorsen ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Critical Role ◽  
Cd4 T Cell ◽  
Macaque Model ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Early Effects ◽  
Early Regeneration

The thymus plays a critical role in the maturation and production of T lymphocytes and is a target of infection by human immunodeficiency virus (HIV) and the related simian immunodeficiency virus (SIV). Using the SIV/macaque model of AIDS, we examined the early effects of SIV on the thymus. We found that thymic infection by SIV resulted in increased apoptosis 7–14 d after infection, followed by depletion of thymocyte progenitors by day 21. A marked rebound in thymocyte progenitors occurred by day 50 and was accompanied by increased levels of cell proliferation in the thymus. Our results demonstrate a marked increase in thymic progenitor activity very early in the course of SIV infection, long before marked declines in peripheral CD4+ T cell counts.

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