Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging tick-borne virus with high fatality and an expanding endemic. Currently, effective anti-SFTSV intervention remains unavailable. Favipiravir (T-705) was recently reported to show in vitro and in animal model antiviral efficacy against SFTSV. Here, we conducted a single-blind, randomized controlled trial to assess the efficacy and safety of T-705 in treating SFTS (Chinese Clinical Trial Registry website, number ChiCTR1900023350). From May to August 2018, laboratory-confirmed SFTS patients were recruited from a designated hospital and randomly assigned to receive oral T-705 in combination with supportive care or supportive care only. Fatal outcome occurred in 9.5% (7/74) of T-705 treated patients and 18.3% (13/71) of controls (odds ratio, 0.466, 95% CI, 0.174–1.247). Cox regression showed a significant reduction in case fatality rate (CFR) with an adjusted hazard ratio of 0.366 (95% CI, 0.142–0.944). Among the low-viral load subgroup (RT-PCR cycle threshold ≥26), T-705 treatment significantly reduced CFR from 11.5 to 1.6% (P = 0.029), while no between-arm difference was observed in the high-viral load subgroup (RT-PCR cycle threshold <26). The T-705-treated group showed shorter viral clearance, lower incidence of hemorrhagic signs, and faster recovery of laboratory abnormities compared with the controls. The in vitro and animal experiments demonstrated that the antiviral efficacies of T-705 were proportionally induced by SFTSV mutation rates, particularly from two transition mutation types. The mutation analyses on T-705-treated serum samples disclosed a partially consistent mutagenesis pattern as those of the in vitro or animal experiments in reducing the SFTSV viral loads, further supporting the anti-SFTSV effect of T-705, especially for the low-viral loads.

With over 80 members worldwide, Orthobunyavirus is the largest genus in the Peribunyaviridae family. Orthobunyaviruses (OBVs) are arthropod-borne viruses that are structurally simple, with a trisegmented, negative-sense RNA genome and only four structural proteins. OBVs are potential agents of emerging and re-emerging diseases and overall represent a global threat to both public and veterinary health. The focus of this review is on the very first steps of OBV infection in mammalian hosts, from virus binding to penetration and release of the viral genome into the cytosol. Here, we address the most current knowledge and advances regarding OBV receptors, endocytosis, and fusion.

Phenuiviridae is a large family of arthropod-borne viruses with over 100 species worldwide. Several cause severe diseases in both humans and livestock. Global warming and the apparent geographical expansion of arthropod vectors are good reasons to seriously consider these viruses potential agents of emerging diseases. With an increasing frequency and number of epidemics, some phenuiviruses represent a global threat to public and veterinary health. This review focuses on the early stage of phenuivirus infection in mammalian host cells. We address current knowledge on each step of the cell entry process, from virus binding to penetration into the cytosol. Virus receptors, endocytosis, and fusion mechanisms are discussed in light of the most recent progress on the entry of banda-, phlebo-, and uukuviruses, which together constitute the three prominent genera in the Phenuiviridae family.

Toscana virus is a major cause of arboviral disease in humans in the Mediterranean basin during summer. However, early virus-host cell interactions and entry mechanisms remain poorly characterized. Investigating iPSC-derived human neurons and cell lines, we found that virus binding to the cell surface was specific, and 50% of bound virions were endocytosed within 10 min. Virions entered Rab5a+ early endosomes and, subsequently, Rab7a+ and LAMP-1+ late endosomal compartments. Penetration required intact late endosomes and occurred within 30 min following internalization. Virus entry relied on vacuolar acidification, with an optimal pH for viral membrane fusion at pH 5.5. The pH threshold increased to 5.8 with longer pre-exposure of virions to the slightly acidic pH in early endosomes. Strikingly, the particles remained infectious after entering late endosomes with a pH below the fusion threshold. Overall, our study establishes Toscana virus as a late-penetrating virus and reveals an atypical use of vacuolar acidity by this virus to enter host cells.

Arenaviruses cause chronic and asymptomatic infections in their natural host, rodents, and several arenaviruses cause severe hemorrhagic fever that has a high mortality in infected humans, seriously threatening public health. There are currently no FDA-licensed drugs available against arenaviruses; therefore, it is important to develop novel antiviral strategies to combat them, which would be facilitated by a detailed understanding of the interactions between the viruses and their hosts. To this end, we performed a transcriptomic analysis on cells infected with arenavirus lymphocytic choriomeningitis virus (LCMV), a neglected human pathogen with clinical significance, and found that the signal transducer and activator of transcription 3 (STAT3) signaling pathway was activated. A further investigation indicated that STAT3 could be activated by the RNA-dependent RNA polymerase L protein (Lp) of LCMV. Our functional analysis found that STAT3 cannot affect LCMV multiplication in A549 cells. We also found that STAT3 was activated by the Lp of Mopeia virus and Junin virus, suggesting that this activation may be conserved across certain arenaviruses. Our study explored the interactions between arenaviruses and STAT3, which may help us to better understand the molecular and cell biology of arenaviruses.

Lien entre la composition moléculaire, l'ultrastructure et l'infectivité des virus Germiston (GERV) dérivés de lignées cellulaires de mammifères et de moustiques: Le genre Orthobunyavirus de la famille des Peribunyaviridae, de l'ordre des Bunyavirales, est un grand groupe de virus transmis par les arthropodes (arbovirus) qui compte plus de 100 membres dans le monde, notamment en Europe occidentale, en Amérique du Nord et du Sud et en Asie. Nombre d'entre eux sont des agents pathogènes émergents qui provoquent des maladies graves, parfois mortelles, chez l'homme et les grands ruminants. Le fait que les orthobunyavirus (OBV), comme d'autres arbovirus, aient un double cycle de vie complexe chez les arthropodes et les vertébrés, implique des différences fondamentales dans la composition moléculaire des particules virales, qu'elles soient produites à partir de cellules d'arthropodes ou de mammifères. La manière dont les caractéristiques moléculaires acquises par les OBV chez les arthropodes influencent l'infection des hôtes mammifères reste largement à découvrir. Dans cette étude, nous avons utilisé le virus Germiston (GERV), un OBV neurotrope transmis par les moustiques, comme système modèle de virus pour étudier le changement d'hôte de l'OBV et les premières étapes de l'infection. Nous avons établi un protocole pour produire de grandes quantités de GERV purifié à partir de cellules de moustiques et de mammifères. En utilisant ces virus, j'ai découvert que les GERV dérivés de cellules de moustiques (mosGERV) sont plus infectieux que ceux produits dans des cellules de mammifères (mamGERV) lorsqu'ils infectent des cellules de mammifères. En détail, les deux GERV s'appuient sur des compartiments endosomaux tardifs intacts pour l'entrée infectieuse, mais la liaison virale semble toutefois plus efficace et la fusion virale plus rapide lorsque le GERV est dérivé de cellules de moustiques plutôt que de cellules de mammifères. L'état de l'organisation structurale des glycoprotéines virales a été analysé par SDS-PAGE et WB. Les résultats indiquent que le mosGERV a un niveau plus élevé de machinerie de fusion à pH neutre. Nous avons également examiné la composition moléculaire des particules de GERV par des approches OMICS. Les méthodes comparatives de lipidomique et de protéomique ont révélé une composition moléculaire distincte, que le GERV soit produit à partir de cellules de moustiques ou de mammifères. Dans l'ensemble, nos résultats indiquent que le mosGERV présente une plus grande infectivité dans les cellules de mammifères que le mamGERV, au moins pendant le processus d'entrée. Notre comparaison moléculaire et fonctionnelle systématique entre les particules virales issues de moustiques et de cellules de mammifères ouvrira de nouveaux horizons dans le domaine des maladies transmises par les arthropodes et ouvrira la voie, non seulement pour répondre à des questions générales en biologie cellulaire, en immunologie et en virologie, mais aussi pour développer des stratégies préventives et antivirales contre les OBV et les virus apparentés.