73 research outputs found
HIV-1 VPR impairs cell growth through the inactivation of two genetically distinct host cell proteins
International audiencen.
The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses.: The HERV family MSRV retrovirus activates innate immunity
rendre public SVPInternational audienceMultiple sclerosis-associated retroviral element (MSRV) is a retroviral element, the sequence of which served to define the W family of human endogenous retroviruses. MSRV viral particles display proinflammatory activities both in vitro in human mononuclear cell cultures and in vivo in a humanized SCID mice model. To understand the molecular basis of such properties, we have investigated the inflammatory potential of the surface unit of the MSRV envelope protein (ENV-SU), the fraction that is poised to naturally interact with host cells. We report in this study that MSRV ENV-SU induces, in a specific manner, human monocytes to produce major proinflammatory cytokines through engagement of CD14 and TLR4, which are pattern recognition receptors of primary importance in innate immunity. ENV-SU could also trigger a maturation process in human dendritic cells. Finally, ENV-SU endowed dendritic cells with the capacity to support a Th1-like type of Th cell differentiation. The data are discussed in the context of immune responses and chronic proinflammatory disorders
Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein
Monoclonal antibodies (mAbs) play an increasing important role in the therapeutic armamentarium against multiple
sclerosis (MS), an inflammatory and degenerative disorder of the central nervous system. Most of the mAbs currently
developed for MS are immunomodulators blocking the inflammatory immune process. In contrast with mAbs targeting
immune function, GNbAC1, a humanized IgG4 mAb, targets the multiple sclerosis associated retrovirus envelope (MSRVEnv)
protein, an upstream factor in the pathophysiology of MS. MSRV-Env protein is of endogenous retroviral origin,
expressed in MS brain lesions, and it is pro-inflammatory and toxic to the remyelination process, by preventing the
differentiation of oligodendrocyte precursor cells. We present the preclinical and early clinical development results of
GNbAC1. The specificity of GNbAC1 for its endogenous retroviral target is described. Efficacy of different mAb versions of
GNbAC1 were assessed in MSRV-Env induced experimental allergic encephalitis (EAE), an animal model of MS. Because
the target MSRV-Env is not expressed in animals, no relevant animal model exists for a proper in vivo toxicological
program. An off-target 2-week toxicity study in mice was thus performed, and it showed an absence of safety risk.
Additional in vitro analyses showed an absence of complement or antibody-dependent cytotoxicity as well as a low level
of cross-reactivity to human tissues. The first-in-man clinical study in 33 healthy subjects and a long-term clinical study in
10 MS patients showed that GNbAC1 is well tolerated in humans without induction of immunogenicity and that it
induces a pharmacodynamic response on MSRV biomarkers. These initial results suggest that the mAb GNbAC1 could be
a safe long-term treatment for patients with MS with a unique therapeutic mechanism of action.GeNeuro SA, Geneva, Switzerlandhttp://www.tandfonline.com/loi/kmab202016-01-31hb201
Inflammatory response of endothelial cells to a human endogenous retrovirus associated with multiple sclerosis is mediated by TLR4.
The MSRV (multiple sclerosis-associated retrovirus) belongs to the human endogenous retrovirus HERV-W family. The envelope protein originating from the MSRV has been found in most patients with multiple sclerosis (MS). This protein (Env-ms) has pro-inflammatory properties for several types of immune cells and could therefore play a role in MS pathogenesis by promoting the leukocyte diapedesis observed in the central nervous system of patients. Our study aims to analyze the effects of Env-ms on the blood-brain barrier (BBB) at a molecular and functional level. We demonstrate that the recombinant MSRV envelope is able to stimulate several inflammatory parameters in a human BBB in vitro model, the HCMEC/D3 brain endothelial cell line. Indeed, Env-ms induces over-expression of ICAM-1, a major mediator of leukocyte adhesion to endothelial cells, in a dose-dependent manner as well as a strong dose-dependent production of the pro-inflammatory cytokines IL-6 and IL-8. Furthermore, using a silencing approach with siRNAs, we show that Env-ms is recognized via the Toll-like receptor 4 receptor, a pattern recognition receptor of innate immunity present on endothelial cells. We also show, using functional assays, that treatment of brain endothelial cells with Env-ms significantly stimulated the adhesion and the transmigration of activated immune cells through a monolayer of endothelial cells. These findings support the hypothesis that MSRV could be involved in the pathogenesis of MS disease or at least in maintenance of inflammatory conditions, thus fueling the auto-immune disorder. MSRV could also play a role in other chronic inflammatory diseases
The envelope of human endogenous retrovirus in neuro-inflammation
International audiencen.
Growth of white matter in the adolescent brain: role of testosterone and androgen receptor
The growth of white matter during human adolescence shows a striking sexual dimorphism; the volume of white matter increases with age slightly in girls and steeply in boys. Here, we provide evidence supporting the role of androgen receptor (AR) in mediating the effect of testosterone on white matter. In a large sample of typically developing adolescents (n = 408, 204 males), we used magnetic resonance imaging and acquired T1-weighted and magnetization transfer ratio (MTR) images. We also measured plasma levels of testosterone and genotyped a functional polymorphism in the AR gene, namely the number of CAG repeats in exon 1 believed to be inversely proportional to the AR transcriptional activity. We found that the testosterone-related increase of white-matter volume was stronger in male adolescents with the lower versus higher number of CAG repeats in the AR gene, with testosterone explaining, respectively, 26 and 8% of variance in the volume. The MTR results suggest that this growth is not related to myelination; the MTR decreased with age in male adolescents. We speculate that testosterone affects axonal caliber rather than the thickness of the myelin sheath
A new therapeutic approach for type 1 diabetes : rationale for GNbAC1, an anti‐HERV‐W‐Env monoclonal antibody
We describe a newly identified therapeutic target for type 1 diabetes (T1D): an envelope protein of endogenous retroviral origin, human endogenous retrovirus W envelope (HERV‐W‐Env). HERV‐W‐Env was found to be detected in the blood of ~60% of patients with T1D and is expressed in acinar pancreatic cells of 75% of patients with T1D at post mortem examination. Preclinical experiments showed that this protein displays direct cytotoxicity on human β‐islet cells. In vivo HERV‐W‐Env impairs the insulin and glucose metabolism in transgenic mice expressing HERV‐W‐Env. GNbAC1, an IgG4 monoclonal antibody, has been developed to specifically target HERV‐W‐Env and to neutralize the effect of HERV‐W‐Env in vitro and in vivo. GNbAC1 is currently in clinical development for multiple sclerosis and > 300 subjects have been administered with GNbAC1 so far. GNbAC1 is now being tested in T1D in the RAINBOW‐T1D study, which is a randomized placebo‐controlled study with the objective of showing the safety and pharmacodynamic response of GNbAC1 in patients who have had T1D with a maximum of 4 years' duration. GNbAC1 is being tested vs placebo at the dose of 6 mg/kg in 60 patients during six repeated administrations for 6 months; a 6‐month open‐label extension will follow. The primary endpoint is to assess safety, and secondary endpoints are the pharmacodynamic responses to GNbAC1. GNbAC1 targeting HERV‐W‐Env is currently in clinical development in T1D, with the first safety and pharmacodynamic study. If the study results are positive, this may open the door to the development of an innovative non‐immunomodulatory disease‐modifying treatment for T1D.The RAINBOW-T1D study is financed by GeNeuro Australia Pty Ltd, a subsidiary of GeNeuro SA, Switzerland.http://wileyonlinelibrary.com/journal/dom2019-09-01hj2018Pharmacolog
Transgenic expression of the HERV-W envelope protein leads to polarized glial cell populations and a neurodegenerative environment.
The human endogenous retrovirus type W (HERV-W) has been identified and repeatedly confirmed as human-specific pathogenic entity affecting many cell types in multiple sclerosis (MS). Our recent contributions revealed the encoded envelope (ENV) protein to disturb myelin repair by interfering with oligodendroglial precursor differentiation and by polarizing microglial cells toward an axon-damage phenotype. Indirect proof of ENV's antiregenerative and degenerative activities has been gathered recently in clinical trials using a neutralizing anti-ENV therapeutic antibody. Yet direct proof of its mode of action can only be presented here based on transgenic ENV expression in mice. Upon demyelination, we observed myelin repair deficits, neurotoxic microglia and astroglia, and increased axon degeneration. Experimental autoimmune encephalomyelitis activity progressed faster in mutant mice equally accompanied by activated glial cells. This study therefore provides direct evidence on HERV-W ENV's contribution to the overall negative impact of this activated viral entity in MS
Induction of Proinflammatory Multiple Sclerosis-Associated Retrovirus Envelope Protein by Human Herpesvirus-6A and CD46 Receptor Engagement
The aberrant expression of human endogenous retrovirus (HERV) elements of the HERV-W family has been associated with different diseases, including multiple sclerosis (MS). In particular, the expression of the envelope protein (Env) from the multiple sclerosis-associated retrovirus (MSRV), a member of HERV-W family and known for its potent proinflammatory activity, is repeatedly detected in the brain lesions and blood of MS patients. Furthermore, human herpesvirus 6 (HHV-6) infection has long been suspected to play a role in the pathogenesis of MS and neuroinflammation. We show here that both HHV-6A and stimulation of its receptor, transmembrane glycoprotein CD46, induce the expression of MSRV-Env. The engagement of extracellular domains SCR3 and SCR4 of CD46-Cyt1 isoform was required for MSRV-env transactivation, limiting thus the MSRV-Env induction to the CD46 ligands binding these domains, including C3b component of complement, specific monoclonal antibodies, and both infectious and UV-inactivated HHV-6A, but neither HHV-6B nor measles virus vaccine strain. Induction of MSRV-Env required CD46 Cyt-1 singling and was abolished by the inhibitors of protein kinase C. Finally, both membrane-expressed and secreted MSRV-Env trigger TLR4 signaling, displaying thus a proinflammatory potential, characteristic for this viral protein. These data expand the specter of HHV-6A effects in the modulation of the immune response and support the hypothesis that cross-talks between exogenous and endogenous viruses may contribute to inflammatory diseases and participate in neuroinflammation. Furthermore, they reveal a new function of CD46, known as an inhibitor of complement activation and receptor for several pathogens, in transactivation of HERV env genes, which may play an important role in the pathogenesis of inflammatory diseases
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