Les virus Hendra (HeV) et Nipah (NiV) sont des virus émergents appartenant à la famille des Paramyxovirus et au genre des Hénipavirus. Chaque année, ils sont responsables de nombreuses épidémies touchant plusieurs espèces animales dont les hommes, avec une forte morbidité et mortalité. À ce jour, aucun vaccin ni traitement ne sont commercialisés. Ce projet porte sur le développement d’un vaccin génétique pour lutter contre une infection par les Hénipavirus. La stratégie suivie, repose sur l’injection in vivo de vecteurs recombinants dérivés du virus Adéno-Associé (AAVr) codant pour la glycoprotéine d’enveloppe G du virus NiV. Une première expérience réalisée chez la souris, a montré qu’une seule injection de vecteurs AAVr par voie IM permet le développement d’une réponse humorale contre la protéine G, forte et stable dans le temps. Afin de tester le pouvoir protecteur de ce vaccin, des hamsters ont été infectés par les Hénipavirus, compte tenu de leur grande sensibilité à ces infections. L’injection de vecteurs AAVr chez ces animaux a permis de protéger 100 % des animaux infectés par le virus NiV et 50 % des animaux infectés par le virus HeV. Cette étude apporte une nouvelle approche de vaccination et de nouvelles perspectives concernant l’utilisation des vecteurs AAVr pour lutter contre des infections virales émergentes. / Nipah virus (NiV) and Hendra virus (HeV) are closely related, recently-emerged Paramyxoviruses, capable of causing considerable morbidity and mortality in several mammalian species, including humans. Commercially available Henipavirus-specific vaccines are still unavailable and development of novel antiviral strategies to prevent this lethal infection is highly desirable. Here we describe the development of Adeno-Associated Virus (AAV) vaccines expressing the NiV G protein. Characterization of these vaccines in mice demonstrated that a single intramuscular AAV injection was sufficient to induce a potent and long lasting antibody response. Translational studies in hamsters further showed that 100 % of vaccinated animals were protected against a lethal challenge with NiV In addition, this vaccine and induced a cross-neutralizing immune response able to protect 50 % of the animals against a challenge HeV. Altogether, this study presents a new vaccination approach which opens new perspectives toward the evaluation of AAV vectors as a vaccine against these emergent diseases.

Simple Summary Gene therapy is a novel approach to treat diseases by introducing corrective genetic information into target cells. Adeno-associated virus vectors are the most frequently applied gene delivery tools for in vivo gene therapy and are also studied as part of innovative anticancer strategies. Here, we report on the natural preference of AAV2 vectors for hepatocellular carcinoma (HCC) compared to nonmalignant liver cells in mice and human tissue. This preference in transduction is due to the improved intracellular processing of AAV2 vectors in HCC, resulting in significantly more vector genomes serving as templates for transcription in the cell nucleus. Based on this natural tropism for HCC, novel therapeutic strategies can be designed or existing therapeutic approaches can be strengthened as they currently result in only a minor improvement of the poor prognosis for most liver cancer patients. Abstract Although therapeutic options are gradually improving, the overall prognosis for patients with hepatocellular carcinoma (HCC) is still poor. Gene therapy-based strategies are developed to complement the therapeutic armamentarium, both in early and late-stage disease. For efficient delivery of transgenes with antitumor activity, vectors demonstrating preferred tumor tropism are required. Here, we report on the natural tropism of adeno-associated virus (AAV) serotype 2 vectors for HCC. When applied intravenously in transgenic HCC mouse models, similar amounts of vectors were detected in the liver and liver tumor tissue. In contrast, transduction efficiency, as indicated by the level of transgene product, was moderate in the liver but was elevated up to 19-fold in mouse tumor tissue. Preferred transduction of HCC compared to hepatocytes was confirmed in precision-cut liver slices from human patient samples. Our mechanistic studies revealed that this preference is due to the improved intracellular processing of AAV2 vectors in HCC, resulting, for example, in nearly 4-fold more AAV vector episomes that serve as templates for gene transcription. Given this background, AAV2 vectors ought to be considered to strengthen current—or develop novel—strategies for treating HCC.