Search

The successive emergence of SARS-CoV-2 Omicron variants has completely changed the modalities of use of therapeutic monoclonal antibodies. Recent in vitro studies indicated that only Sotrovimab has maintained partial activity against BQ.1.1 and XBB.1. In the present study, we used the hamster model to determine whether Sotrovimab retains antiviral activity against these Omicron variants in vivo. Our results show that at exposures consistent with those observed in humans, Sotrovimab remains active against BQ.1.1 and XBB.1, although for BQ.1.1 the efficacy is lower than that observed against the first globally dominant Omicron sublineages BA.1 and BA.2.

Drug repositioning has been used extensively since the beginning of the COVID-19 pandemic in an attempt to identify antiviral molecules for use in human therapeutics. Hydroxychloroquine and azithromycin have shown inhibitory activity against SARS-CoV-2 replication in different cell lines. Based on such in vitro data and despite the weakness of preclinical assessment, many clinical trials were set up using these molecules. In the present study, we show that hydroxychloroquine and azithromycin alone or combined does not block SARS-CoV-2 replication in human bronchial airway epithelia. When tested in a Syrian hamster model, hydroxychloroquine and azithromycin administrated alone or combined displayed no significant effect on viral replication, clinical course of the disease and lung impairments, even at high doses. Hydroxychloroquine quantification in lung tissues confirmed strong exposure to the drug, above in vitro inhibitory concentrations. Overall, this study does not support the use of hydroxychloroquine and azithromycin as antiviral drugs for the treatment of SARS-CoV-2 infections.

Following the emergence of SARS-CoV-2, the search for an effective and rapidly available treatment was initiated worldwide based on repurposing of available drugs. Previous reports described the antiviral activity of certain tyrosine kinase inhibitors (TKIs) targeting the Abelson kinase 2 against pathogenic coronaviruses. Imatinib, one of them, has more than twenty years of safe utilization for the treatment of hematological malignancies. In this context, Imatinib was rapidly evaluated in clinical trials against Covid-19. Here, we present the pre-clinical evaluation of Imatinib in multiple models. Our results indicated that Imatinib and another TKI, the Masitinib, exhibit an antiviral activity in VeroE6 cells. However, Imatinib was inactive in a reconstructed bronchial human airway epithelium model. In vivo, Imatinib therapy failed to impair SARS-CoV-2 replication in a golden Syrian hamster model despite high concentrations in plasma and in the lung. Overall, these results do not support the use of Imatinib and similar TKIs as antivirals in the treatment of Covid-19.

The flavivirus, tick-borne encephalitis virus (TBEV) is transmitted by Ixodes spp. ticks and may cause severe and potentially lethal neurological tick-borne encephalitis (TBE) in humans. Studying TBEV requires the use of secondary methodologies to detect the virus in infected cells. To overcome this problem, we rationally designed and constructed a recombinant reporter TBEV that stably expressed the mCherry reporter protein. The resulting TBEV reporter virus (named mCherry-TBEV) and wild-type parental TBEV exhibited similar growth kinetics in cultured cells; however, the mCherry-TBEV virus produced smaller plaques. The magnitude of mCherry expression correlated well with progeny virus production but remained stable over

Arbidol (ARB) is an antiviral drug originally licensed in Russia for use against influenza and other respiratory viral infections. Although a broad-spectrum antiviral activity has been reported for this drug, there is until now no data regarding its effects against alphavirus infection. Here, the in vitro antiviral effect of ARB on Chikungunya virus (CHIKV) replication was investigated and this compound was found to present potent inhibitory activity against the virus propagated onto immortalized Vero cells or primary human fibroblasts (MRC-5 lung cells) (IC50 < 10 mu g/ml). A CHIKV resistant mutant was then selected and adapted to growth in the presence of 30 mu g/ml ARB in MRC5 cells; its complete sequence analysis revealed a single amino acid substitution (G407R) localized in the E2 envelope protein. To confirm the G407R role in the molecular mechanism of ARB resistance, a CHIKV infectious clone harboring the same substitution was engineered, tested, and was found to display a similar level of resistance. Finally, our results demonstrated the effective in vitro antiviral activity of ARB against CHIKV and gave some tracks to understand the molecular basis of ARB activity.

The arenaviruses and hantaviruses are segmented genome RNA viruses that are hosted by rodents. Due to their association with rodents, they are globally widespread and can infect humans via direct or indirect routes of transmission, causing considerable human morbidity and mortality. Nevertheless, despite their obvious and emerging importance as pathogens, there are currently no effective antiviral drugs (except ribavirin which proved effective against Lassa virus) with which to treat humans infected by any of these viruses. The EU-funded VIZIER project (Comparative Structural Genomics of Viral Enzymes Involved in Replication) was instigated with an ultimate view of contributing to the development of antiviral therapies for RNA viruses, including the arenaviruses and bunyaviruses. This review highlights some of the major features of the arenaviruses and hantaviruses that have been investigated during recent years. After describing their classification and epidemiology, we review progress in understanding the genomics as well as the structure and function of replicative enzymes achieved under the VIZIER program and the development of new disease control strategies.

The genus Flavivirus contains approximately 70 arthropod-borne enveloped RNA viruses many of which cause severe human and in some cases, animal disease. They include dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, and tick-borne encephalitis virus. Hundreds of thousands of deaths due to flavivirus infections occur each year, many of which are unpreventable due to lack of availability of appropriate vaccines and/or antiviral drugs. Flaviviruses exploit the cytoplasmic cellular machinery to facilitate propagation of infectious progeny virions. They engage in dynamic and antagonistic interactions with host cell membranes and biochemical processes. Following infection, the cells initiate various antiviral strategies to counteract viral invasion. In its defense, the virus has alternative strategies to suppress these host responses to infection. The fine balance between these interactions determines the outcome of the viral infection and disease progression. Published studies have revealed specific effects of flaviviruses on cellular processes, but the underlying mechanisms that determine the specific cytopathogenetic changes induced by different flaviviruses have not, as yet, been elucidated. Independently of the suppression of the type I IFN response which has been described in detail elsewhere, this review focuses on recent discoveries relating to alterations of host metabolism following viral infection. Such studies may contribute to new approaches to antiviral drug development. The role of host cellular factors will be examined in the context of protection and/or pathogenesis resulting from flavivirus infection, with particular emphasis on West Nile virus and dengue virus.

Highlights • Chikungunya fever is caused by a mosquito-borne alphavirus originating in East Africa. • During the past 7 years, the disease has spread to islands of the Indian Ocean, Asia and Europe. • Its spread has been facilitated by a mutation favouring replication in the mosquito Ae. albopictus. • No vaccines or antiviral drugs are available to prevent or treat chikungunya fever. • This paper provides an extensive review of the virus and disease, including Supplementary Tables., Chikungunya virus (CHIKV) is the aetiological agent of the mosquito-borne disease chikungunya fever, a debilitating arthritic disease that, during the past 7 years, has caused immeasurable morbidity and some mortality in humans, including newborn babies, following its emergence and dispersal out of Africa to the Indian Ocean islands and Asia. Since the first reports of its existence in Africa in the 1950s, more than 1500 scientific publications on the different aspects of the disease and its causative agent have been produced. Analysis of these publications shows that, following a number of studies in the 1960s and 1970s, and in the absence of autochthonous cases in developed countries, the interest of the scientific community remained low. However, in 2005 chikungunya fever unexpectedly re-emerged in the form of devastating epidemics in and around the Indian Ocean. These outbreaks were associated with mutations in the viral genome that facilitated the replication of the virus in Aedes albopictus mosquitoes. Since then, nearly 1000 publications on chikungunya fever have been referenced in the PubMed database. This article provides a comprehensive review of chikungunya fever and CHIKV, including clinical data, epidemiological reports, therapeutic aspects and data relating to animal models for in vivo laboratory studies. It includes Supplementary Tables of all WHO outbreak bulletins, ProMED Mail alerts, viral sequences available on GenBank, and PubMed reports of clinical cases and seroprevalence studies.

Highlights • We review the history of major technologic breakthroughs in reverse genetics methods for flavivirus research. • We inventory the current reverse genetics systems for the study of flaviviruses. • We describe the different strategies developed to overcome technical hurdles. • We review significant applications developed using flavivirus reverse genetics systems., The study of flaviviruses, which cause some of the most important emerging tropical and sub-tropical human arbovirus diseases, has greatly benefited from the use of reverse genetic systems since its first development for yellow fever virus in 1989. Reverse genetics technology has completely revolutionized the study of these viruses, making it possible to manipulate their genomes and evaluate the direct effects of these changes on their biology and pathogenesis. The most commonly used reverse genetics system is the infectious clone technology. Whilst flavivirus infectious clones provide a powerful tool, their construction as full-length cDNA molecules in bacterial vectors can be problematic, laborious and time consuming, because they are often unstable, contain unwanted induced substitutions and may be toxic for bacteria due to viral protein expression. The incredible technological advances that have been made during the past 30 years, such as the use of PCR or new sequencing methods, have allowed the development of new approaches to improve preexisting systems or elaborate new strategies that overcome these problems. This review summarizes the evolution and major technical breakthroughs in the development of flavivirus reverse genetics technologies and their application to the further understanding and control of these viruses and their diseases.