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The Flavivirus genus includes a number of important viruses that are pathogenic to humans and animals and are responsible for outbreaks across the globe. Integrins, a family of heterodimeric transmembrane molecules expressed in all nucleated cells mediate critical functions of cell physiology and cell cycle. Integrins were previously postulated to be involved in flavivirus entry and to modulate flavivirus replication efficiency. In the present study, mouse embryonic fibroblasts (MEF), lacking the expression of αVβ3 integrin (MEF-αVβ3−/−), were infected with four different flaviviruses, namely yellow fever virus (YFV), West Nile virus (WNV), Usutu virus (USUV) and Langat virus (LGTV). The effects of the αVβ3 integrin absence in double-knockout MEF-αVβ3−/− on flavivirus binding, internalization and replication were compared to the respective wild-type cells. Binding to the cell surface for all four flaviviruses was not affected by the ablation of αVβ3 integrin, whereas internalization of USUV and WNV was slightly affected by the loss of αVβ3 integrin expression. Most interestingly, the deletion of αVβ3 integrin strongly impaired replication of all flaviviruses with a reduction of up to 99% on virus yields and a strong reduction on flavivirus anti-genome RNA synthesis. In conclusion, our results demonstrate that αVβ3 integrin expression in flavivirus-susceptible cell lines enhances the flavivirus replication.

Influenza A virus (IAV) is a common pathogen of respiratory disease. The IAV-induced seasonal epidemics and the sporadic pandemics are associated with high morbidity and mortality. Therefore, effective protection and therapy for IAV infections is an important challenge in countering this public health threat. Because vaccinations only protect against known circulating strains, and the currently available antivirals pose the risk of resistance formation, drugs targeting host cell factors needed for viral replication offer a promising therapeutic approach. In this study, we describe the use of the antifungal therapeutics posaconazole and itraconazole in the therapy of IAV. We show that both drugs efficiently inhibit the propagation of IAV in the cell culture model without being cytotoxic. The mode of action is probably based on several targets and includes both a priming of the interferon response and the induced imbalance of cellular cholesterol. The antiviral effect of itraconazole could be confirmed in the mouse model, where the administration of itraconazole led to a drastic reduction in mortality and a significant increase in the survival rate. Thus, our data indicate a promising therapeutic potential of at least itraconazole in influenza therapy.

The Arenaviridae family consists of a large group of single strand ambisense RNA viruses that are separated phylogenetically, serologically and geographically into Old World and New World viruses. Recent studies indicate that cellular entry of arenaviruses requires a series of cellular protein interaction and molecular mechanisms. The arenaviruses entry into cells is initiated by the interaction of viral glycoprotein with one or more receptors on the surface of host cells. The main host cell factors that are involved in filovirus entry are attachment factors (α-dystroglycan for Old World and human transferrin receptor 1 for New World viruses), endolisosomal host cell factors (cathepsins B and L and Niemann-Pick C1 protein). The review presents the modern knowledge about the role of structural proteins of arenaviruses and some cell factors in pathogenesis of the diseases, caused by arenaviruses.

Highlights • Many emerging or known, chronic viral diseases are caused by enveloped viruses. • The review discusses research driven development of antivirals that became recently available or are in clinical evaluation. • The main focus is on antiviral strategies with a broader therapeutic range, and on novel immune based therapeutics. • Broad-spectrum antivirals will help to react faster to newly emerging viral diseases. • Targeting immune cells against infected cells can restore immune responses in chronic infections., Enveloped viruses pose an important health threat because most of the persistent and many emerging viruses are enveloped. In particular, newly emerging viruses create a need to develop broad-spectrum antivirals, which usually are obtained by targeting host cell factors. Persistent viruses have developed efficient strategies to escape host immune control, and treatment options are limited. Targeting host cell factors essential for virus persistence, or immune-based therapies provide alternative approaches. In this review, we therefore focus on recent developments to generate antivirals targeting host cell factors or immune-based therapeutic approaches to fight infections with enveloped viruses.

Background ZASC1 is a zinc finger-containing transcription factor that was previously shown to bind to specific DNA binding sites in the Moloney murine leukemia virus (Mo-MuLV) promoter and is required for efficient viral mRNA transcription (J. Virol. 84:7473-7483, 2010). Methods To determine whether this cellular factor influences Mo-MuLV replication and viral disease pathogenesis in vivo, we generated a ZASC1 knockout mouse model and completed both early infection and long term disease pathogenesis studies. Results Mice lacking ZASC1 were born at the expected Mendelian ratio and showed no obvious physical or behavioral defects. Analysis of bone marrow samples revealed a specific increase in a common myeloid progenitor cell population in ZASC1-deficient mice, a result that is of considerable interest because osteoclasts derived from the myeloid lineage are among the first bone marrow cells infected by Mo-MuLV (J. Virol. 73: 1617-1623, 1999). Indeed, Mo-MuLV infection of neonatal mice revealed that ZASC1 is required for efficient early virus replication in the bone marrow, but not in the thymus or spleen. However, the absence of ZASC1 did not influence the timing of subsequent tumor progression or the types of tumors resulting from virus infection. Conclusions These studies have revealed that ZASC1 is important for myeloid cell differentiation in the bone marrow compartment and that this cellular factor is required for efficient Mo-MuLV replication in this tissue at an early time point post-infection.