Prospects for prophylactic hepatitis C vaccines based on virus-like particles.

International audienceGiven the global prevalence and long-term complications of chronic hepatitis C virus (HCV) infection, HCV constitutes one of the greatest challenges to human health of this decade. Considerable efforts have focused on the development of new effective treatments, but about three to four million individuals become infected each year, adding to the world reservoir of HCV infection. The development of a prophylactic vaccine against hepatitis C virus has thus become an important medical priority. Only a few vaccine candidates have progressed to the clinical phase, and published data on both the efficacy and safety of these vaccines are limited, due to many scientific, logistic and bioethic challenges. Fortunately, new innovative vaccine formulations, modes of vaccination and delivery technologies have been developed in recent years. Several preclinical trials of virus-like particle (VLP)-based vaccination strategies are currently underway and have already generated very promising results. In this commentary, we consider the current state of prophylactic HCV vaccines, the hurdles to be overcome in the future and the various VLP-based vaccination approaches currently being developed

Chimeric hepatitis B virus/hepatitis C virus envelope proteins elicit broadly neutralizing antibodies and constitute a potential bivalent prophylactic vaccine.

International audienceThe development of a prophylactic vaccine against hepatitis C virus (HCV) has become an important medical priority, because 3-4 million new HCV infections are thought to occur each year worldwide. Hepatitis B virus (HBV) is another major human pathogen, but infections with this virus can be prevented with a safe, efficient vaccine, based on the remarkable ability of the envelope protein (S) of this virus to self-assemble into highly immunogenic subviral particles. Chimeric HBV-HCV envelope proteins in which the N-terminal transmembrane domain of S was replaced with the transmembrane domain of the HCV envelope proteins (E1 or E2) were efficiently coassembled with the wild-type HBV S protein into subviral particles. These chimeric particles presented the full-length E1 and E2 proteins from a genotype 1a virus in an appropriate conformation for formation of the E1-E2 heterodimer. Produced in stably transduced Chinese hamster ovary cells and used to immunize New Zealand rabbits, these particles induced a strong specific antibody (Ab) response against the HCV and HBV envelope proteins in immunized animals. Sera containing anti-E1 or anti-E2 Abs elicited by these particles neutralized infections with HCV pseudoparticles and cell-cultured viruses derived from different heterologous 1a, 1b, 2a, and 3 strains. Moreover, the anti-hepatitis B surface response induced by these chimeric particles was equivalent to the response induced by a commercial HBV vaccine. Conclusions: Our results provide support for approaches based on the development of bivalent HBV-HCV prophylactic vaccine candidates potentially able to prevent initial infection with either of these two hepatotropic viruses. (HEPATOLOGY 2013)

Sequential biogenesis of host cell membrane rearrangements induced by hepatitis C virus infection.: HCV-induced membrane rearrangements

International audienceLike most positive-strand RNA viruses, hepatitis C virus (HCV) forms a membrane-associated replication complex consisting of replicating RNA, viral and host proteins anchored to altered cell membranes. We used a combination of qualitative and quantitative electron microscopy (EM), immuno-EM, and the 3D reconstruction of serial EM sections to analyze the host cell membrane alterations induced by HCV. Three different types of membrane alteration were observed: vesicles in clusters (ViCs), contiguous vesicles (CVs), and double-membrane vesicles (DMVs). The main ultrastructural change observed early in infection was the formation of a network of CVs surrounding the lipid droplets. Later stages in the infectious cycle were characterized by a large increase in the number of DMVs, which may be derived from the CVs. These DMVs are thought to constitute the membranous structures harboring the viral replication complexes in which viral replication is firmly and permanently established and to protect the virus against double-stranded RNA-triggered host antiviral responses

IL-26, a Cytokine With Roles in Extracellular DNA-Induced Inflammation and Microbial Defense

Interleukin 26 (IL-26) is the most recently identified member of the IL-20 cytokine subfamily, and is a novel mediator of inflammation overexpressed in activated or transformed T cells. Novel properties have recently been assigned to IL-26, owing to its non-conventional cationic, and amphipathic features. IL-26 binds to DNA released from damaged cells and, as a carrier molecule for extracellular DNA, links DNA to inflammation. This observation suggests that IL-26 may act both as a driver and an effector of inflammation, leading to the establishment of a deleterious amplification loop and, ultimately, sustained inflammation. Thus, IL-26 emerges as an important mediator in local immunity/inflammation. The dysregulated expression and extracellular DNA carrier capacity of IL-26 may have profound consequences for the chronicity of inflammation. IL-26 also exhibits direct antimicrobial properties. This review summarizes recent advances on the biology of IL-26 and discusses its roles as a novel kinocidin

GOLIAH (Gaming Open Library for Intervention in Autism at Home): a 6-month single blind matched controlled exploratory study

BackgroundTo meet the required hours of intensive intervention for treating children with autism spectrum disorder (ASD), we developed an automated serious gaming platform (11 games) to deliver intervention at home (GOLIAH) by mapping the imitation and joint attention (JA) subset of age-adapted stimuli from the Early Start Denver Model (ESDM) intervention. Here, we report the results of a 6-month matched controlled exploratory study.MethodsFrom two specialized clinics, we included 14 children (age range 5–8 years) with ASD and 10 controls matched for gender, age, sites, and treatment as usual (TAU). Participants from the experimental group received in addition to TAU four 30-min sessions with GOLIAH per week at home and one at hospital for 6 months. Statistics were performed using Linear Mixed Models.ResultsChildren and parents participated in 40% of the planned sessions. They were able to use the 11 games, and participants trained with GOLIAH improved time to perform the task in most JA games and imitation scores in most imitation games. GOLIAH intervention did not affect Parental Stress Index scores. At end-point, we found in both groups a significant improvement for Autism Diagnostic Observation Schedule scores, Vineland socialization score, Parental Stress Index total score, and Child Behavior Checklist internalizing, externalizing and total problems. However, we found no significant change for by time × group interaction.ConclusionsDespite the lack of superiority of TAU + GOLIAH versus TAU, the results are interesting both in terms of changes by using the gaming platform and lack of parental stress increase. A large randomized controlled trial with younger participants (who are the core target of ESDM model) is now discussed. This should be facilitated by computing GOLIAH for a web platform.Trial registration Clinicaltrials.gov NCT0256041

Age at onset as stratifier in idiopathic Parkinson’s disease – effect of ageing and polygenic risk score on clinical phenotypes

Several phenotypic differences observed in Parkinson’s disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients

Study of the in vivo emergence of a Human Immunodefiency virus type 1 variant carrying glycoproteins naturally truncated in their cytoplasmic domain

Les glycoprotéines d'enveloppe (Env) du VIH-1 se caractérisent par leur long domaine cytoplasmique (DC) qui joue un rôle essentiel dans la morphogenèse et l’infectivité virales. La multiplication virale in vitro et in vivo dépend ainsi étroitement de l’intégrité de ce domaine. Nous avons cependant identifié un patient infecté par un VIH-1 présentant des Env avec un DC tronqué de 20 acides aminés. Cette anomalie structurale aurait dû aboutir à la production de virions dont la capacité infectieuse était fortement diminuée. Mon travail de thèse a donc consisté à évaluer les conséquences fonctionnelles d’une telle troncation et à explorer les mécanismes moléculaires permettant au virus présentant cette anomalie de se multiplier efficacement in vivo. Les travaux réalisés au cours de cette thèse ont abouti à l’identification de mécanismes de compensation des capacités de multiplication de ce virus portant des Env tronquées dans leur DC impliquant des mutations dans la protéine de matrice. En conclusion, toutes ces données ont permis d’apporter des éléments de compréhension nouveaux quant à l’assemblage du VIH-1 et son fort potentiel d’évolution in vivo.The human immunodeficiency virus type 1 (HIV-1) typically encodes envelope glycoprotein transmembrane subunits with long cytoplasmic tails (CTs) involved in viral infectivity and morphogenesis. The integrity of the gp41 CT thus seems to be essential for viral replication in vitro and in vivo. However, we report here the emergence and dominance in vivo of a primary HIV-1 variant carrying a natural 20-amino-acid truncation of the gp41 CT. Such a deletion would therefore be expected to impair viral replication. The aims of this study were thus to assess the functional consequences of the gp41 truncation and to identify the molecular mechanisms by which a primary HIV-1 harboring such a deletion in the gp41 CT maintained its ability to replicate efficiently in vivo. Our findings reveal that replication capacity of a primary HIV-1 carrying truncated CT could be rescued by compensatory mechanisms involving mutations in the matrix protein. In conclusion, our findings provide new insignt into HIV-1 assembly and evolution potential in vivo

Chimeric hepatitis B virus (HBV)/hepatitis C virus (HCV) subviral envelope particles induce efficient anti-HCV antibody production in animals pre-immunized with HBV vaccine

International audienceThe development of an effective, affordable prophylactic vaccine against hepatitis C virus (HCV) remains a medical priority. The recently described chimeric HBV-HCV subviral envelope particles could potentially be used for this purpose, as they could be produced by industrial procedures adapted from those established for the hepatitis B virus (HBV) vaccine. We show here, in an animal model, that pre-existing immunity acquired through HBV vaccination does not influence the immunogenicity of the HCV E2 protein presented by these chimeric particles. Thus, these chimeric HBV-HCV subviral envelope particles could potentially be used as a booster in individuals previously vaccinated against HBV, to induce protective immunity to HCV