Search

A 39 years old homosexual male suffering from chronic type B hepatitis superinfected by HDV, and positive for anti-HIV1 was treated with zidovudine associated with high doses of recombinant interferon alpha for onset of an extensive cutaneous Kaposi sarcoma. Other than the long-lasting disappearance of Kaposi's lesions, this therapy was followed by complete recovery from hepatitis B and D. Serological and hepatic clearance of both viruses was marked by two successive cytolytic peaks separated by a 9 month interval. The patient's immunologic status has remained stable at 30 months. To our knowledge, such a success had never been reported in the literature and the clearance of both hepatitis B and D viruses in an AIDS patient stands in sharp contrast with the usual rapidly progressive evolution of those triple coinfections. This phenomenon illustrates the potential benefits of zidovudine in association with high dose of interferon alpha in HIV patients suffering from hepatitis D.

Several viruses of the Flaviviridae family are causing agents of human pathologies, including haemorrhagic fever (e.g. Dengue virus, Yellow fever virus), encephalitis (e.g. Japanese encephalitis virus), or chronic hepatitis (Hepatitis C virus). For most of these diseases, while no vaccine have been developed to date, either no or non optimal treatments are currently available. New antivirals are needed to better combat Flaviviridae induced diseases. Molecules targeting specifically viral enzymes are the most attractive in terms of drug development and are therefore the most studied. However, an antiviral strategy based uniquely on the utilisation of this type of molecules is expected to encounter problems caused by the emergence of viral escape mutants, as already widely described for HIV and HBV. Alternative approaches would include targeting either a viral function that is less likely to give rise to viral escape mutants, or a host cell encoded function that would be crucial for the virus, but not for the cell itself. The viral assembly and morphogenesis belong to these new potential targets yet not exploited. Recently inhibitors of morphogenesis have been identified and studied in different virus/cell systems. Some of them are currently evaluated in clinical trials against HCV. The present review focuses on the Flaviviridae morphogenesis and its inhibition; and presents clinical development perspectives of this new generation of antivirals.La famille des Flaviviridae regroupe des virus enveloppés à ARN simple brin de polarité positive responsables de nombreuses pathologies humaines et animales. Trois genres constituent cette famille : le genre des flavivirus qui comprend, entre autres, les virus West Nile (WNV), de la fièvre jaune (YFV), de la dengue (DEN), de l’encéphalite japonaise (JEV) et de l’encéphalite transmise par les tiques (TBE) ; celui des pestivirus qui inclut les virus de la diarrhée bovine (VDBV), un virus souvent utilisé comme modèle d’étude du HCV et de la peste porcine classique (CSFV) et, enfin, le genre des hépacivirus qui comprend notamment les différents génotypes et sous-types du virus de l’hépatite C (HCV) [1]. En dépit de leur impact sur la santé humaine, il n’existe pas à l’heure actuelle de traitements antiviraux spécifiques et efficaces pour combattre les infections à flavivirus. En ce qui concerne les infections liées au HCV, un traitement associant l’interféron alpha (IFNα) et la ribavirine permet d’obtenir un taux élevé de réponse virologique prolongée (50-60 %) [2]. Cependant, ce traitement est assez mal toléré en raison des nombreux effets secondaires et, de plus, est très onéreux, ce qui limite son utilisation aux pays développés. Par conséquent, il est urgent et indispensable de développer de nouveaux antiviraux afin de mieux combattre les infections liées aux Flaviviridae. La morphogenèse est une étape clé du cycle viral et représente par conséquent une cible intéressante, encore non exploitée, pour le développement de nouvelles stratégies antivirales. Récemment, des molécules inhibant la morphogenèse virale ont été identifiées et leurs mécanismes d’action étudiés en systèmes cellulaires et animaux. Certaines de ces molécules ont été évaluées ou sont en cours d’évaluation dans le cadre d’essais cliniques sur l’homme. L’objectif de cette revue est de faire un bref état des lieux sur la morphogenèse des Flaviviridae et son inhibition par des antiviraux de nouvelles générations.

The diagnostic value of preS antigens and anti-preS antibodies during Hepatitis B virus (HBV) infections have not yet been clearly elucidated. Therefore, the objectives of this study were: 1) to better understand the clinical significance of the expression of both preS1 and preS2 antigens (preS1Ag and preS2Ag) in the serum of chronic HBsAg carriers, and 2) to define the respective role of antibody responses to HBs-, preS2- and preS1-specific determinants in the course of acute hepatitis B (AH-B) infections with different outcomes. Our data showed that the serum preS1Ag/HBsAg ratio correlated well with the level of viral replication (serum HBV-DNA as monitored by PCR assay and liver HBcAg), especially in anti-HBe positive chronic carriers. The complete eradication of virions required a persistent antibody response to conformation-dependent HBs-epitopes, temporally associated with a vigorous T cell response to nucleocapsid antigens. Recovery from hepatitis B can be achieved when there is no early antibody response to preS2- and preS1-proteins, which was found to be transient, concomitant with a flare-up of the liver disease, and preceding anti-HBs production. Information on the patterns of preS antigens and their antibodies remained clouded because of the varying specificities and sensitivities of research methods used in studies to date. We have, therefore, developed original Polyclonal-Monoclonal RadioImmunoAssays (PAb-MAb RIAs) by using monoclonal antibodies (MAbs) having previously well-defined specificities. We could thus detect and quantify simultaneously the three distinct antigenicities of the HBV envelope, HBsAg, preS2Ag and preS1Ag, with the same sensitivity. In this way, the preS1Ag/HBsAg and preS2Ag/HBsAg ratios can be calculated to estimate the serum expression of both preS1Ag and preS2Ag in relation to total HBsAg activity during different stages of chronic HBV infection. For optimal management of the state of HBV replication in chronic viral infection, the detection of HBV-DNA in serum was monitored by the Polymerase Chain Reaction (PCR) assay. We extended our work by investigating the clinical significance of antibody response to preS-specific determinants in patients with AH-B showing different outcomes in both natural course or response to alpha-interferon therapy. In a first attempt, we chose to use the Western Immuno-Blotting Assay (WIBA) to obtain a qualitative assessment of the nature of preS antibody responses. Finally, the cell-mediated immune response to HBV antigens was also studied in several patients with self-limited AH-B leading to a relevant finding which may help to clarify the mechanisms responsible for complete clearance of HBV.