Novel Antiviral Molecules against Ebola Virus Infection.

Infection with Ebola virus (EBOV) is responsible for hemorrhagic fever in humans with a high mortality rate. Combined efforts of prevention and therapeutic intervention are required to tackle highly variable RNA viruses, whose infections often lead to outbreaks. Here, we have screened the 2P2I3D chemical library using a nanoluciferase-based protein complementation assay (NPCA) and isolated two compounds that disrupt the interaction of the EBOV protein fragment VP35IID with the N-terminus of the dsRNA-binding proteins PKR and PACT, involved in IFN response and/or intrinsic immunity, respectively. The two compounds inhibited EBOV infection in cell culture as well as infection by measles virus (MV) independently of IFN induction. Consequently, we propose that the compounds are antiviral by restoring intrinsic immunity driven by PACT. Given that PACT is highly conserved across mammals, our data support further testing of the compounds in other species, as well as against other negative-sense RNA viruses.

BTN3A3 evasion promotes the zoonotic potential of influenza A viruses.

Spillover events of avian influenza A viruses (IAVs) to humans could represent the first step in a future pandemic1. Several factors that limit the transmission and replication of avian IAVs in mammals have been identified. There are several gaps in our understanding to predict which virus lineages are more likely to cross the species barrier and cause disease in humans1. Here, we identified human BTN3A3 (butyrophilin subfamily 3 member A3)2 as a potent inhibitor of avian IAVs but not human IAVs. We determined that BTN3A3 is expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts primarily at the early stages of the virus life cycle by inhibiting avian IAV RNA replication. We identified residue 313 in the viral nucleoprotein (NP) as the genetic determinant of BTN3A3 sensitivity (313F or, rarely, 313L in avian viruses) or evasion (313Y or 313V in human viruses). However, avian IAV serotypes, such as H7 and H9, that spilled over into humans also evade BTN3A3 restriction. In these cases, BTN3A3 evasion is due to substitutions (N, H or Q) in NP residue 52 that is adjacent to residue 313 in the NP structure3. Thus, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.

The Fate of Speckled Protein 100 (Sp100) During Herpesviruses Infection.

The constitutive expression of Speckled-100 (Sp100) is known to restrict the replication of many clinically important DNA viruses. This pre-existing (intrinsic) immune defense to virus infection can be further upregulated upon interferon (IFN) stimulation as a component of the innate immune response. In humans, Sp100 is encoded by a single gene locus, which can produce alternatively spliced isoforms. The widely studied Sp100A, Sp100B, Sp100C and Sp100HMG have functions associated with the transcriptional regulation of viral and cellular chromatin, either directly through their characteristic DNA-binding domains, or indirectly through post-translational modification (PTM) and associated protein interaction networks. Sp100 isoforms are resident component proteins of promyelocytic leukemia-nuclear bodies (PML-NBs), dynamic nuclear sub-structures which regulate host immune defenses against many pathogens. In the case of human herpesviruses, multiple protein antagonists are expressed to relieve viral DNA genome transcriptional silencing imposed by PML-NB and Sp100-derived proteinaceous structures, thereby stimulating viral propagation, pathogenesis, and transmission to new hosts. This review details how different Sp100 isoforms are manipulated during herpesviruses HSV1, VZV, HCMV, EBV, and KSHV infection, identifying gaps in our current knowledge, and highlighting future areas of research.