Matthias Götte

Resistance patterns associated with HCV NS5A inhibitors provide limited insight into drug binding.

Direct-acting antivirals (DAAs) have significantly improved the treatment of infection with the hepatitis C virus. A promising class of novel antiviral agents targets the HCV NS5A protein. The high potency and broad genotypic coverage are favorable properties. NS5A inhibitors are currently assessed in advanced clinical trials in combination with viral polymerase inhibitors and/or viral protease inhibitors. However, the clinical use of NS5A inhibitors is also associated with new challenges. HCV variants with decreased susceptibility to these drugs can emerge and compromise therapy. In this review, we discuss resistance patterns in NS5A with focus prevalence and implications for inhibitor binding.

Zika virus hijacks stress granule proteins and modulates the host stress response

ABSTRACT Zika virus (ZIKV), a member of the Flaviviridae family, has recently emerged as an important human pathogen with increasing economic and health impact worldwide. Because of its teratogenic nature and association with the serious neurological condition Guillain-Barré syndrome, a tremendous amount of effort has focused on understanding ZIKV pathogenesis. To gain further insights into ZIKV interaction with host cells, we investigated how this pathogen affects stress response pathways. While ZIKV infection induces stress signaling that leads to phosphorylation of eIF2α and cellular translational arrest, stress granule (SG) formation was inhibited. Further analysis revealed that the viral proteins NS3 and NS4A are linked to translational repression, whereas expression of the capsid protein, NS3/NS2B-3, and NS4A interfered with SG formation. Some, but not all, flavivirus capsid proteins also blocked SG assembly, indicating differential interactions between flaviviruses and SG biogenesis pathways. Depletion of the SG components G3BP1, TIAR, and Caprin-1, but not TIA-1, reduced ZIKV replication. Both G3BP1 and Caprin-1 formed complexes with capsid, whereas viral genomic RNA stably interacted with G3BP1 during ZIKV infection. Taken together, these results are consistent with a scenario in which ZIKV uses multiple viral components to hijack key SG proteins to benefit viral replication. IMPORTANCE There is a pressing need to understand ZIKV pathogenesis in order to advance the development of vaccines and therapeutics. The cellular stress response constitutes one of the first lines of defense against viral infection; therefore, understanding how ZIKV evades this antiviral system will provide key insights into ZIKV biology and potentially pathogenesis. Here, we show that ZIKV induces the stress response through activation of the UPR (unfolded protein response) and PKR (protein kinase R), leading to host translational arrest, a process likely mediated by the viral proteins NS3 and NS4A. Despite the activation of translational shutoff, formation of SG is strongly inhibited by the virus. Specifically, ZIKV hijacks the core SG proteins G3BP1, TIAR, and Caprin-1 to facilitate viral replication, resulting in impaired SG assembly. This process is potentially facilitated by the interactions of the viral RNA with G3BP1 as well as the viral capsid protein with G3BP1 and Caprin-1. Interestingly, expression of capsid proteins from several other flaviviruses also inhibited SG formation. Taken together, the present study provides novel insights into how ZIKV modulates cellular stress response pathways during replication.

Tunneling Magnetoresistance Devices Based on Topological Insulators: Ferromagnet–Insulator–Topological-Insulator Junctions Employing Bi2Se3

We theoretically investigate tunneling magnetoresistance (TMR) devices, which are probing the spin-momentum coupled nature of surface states of the three-dimensional topological insulator Bi2Se3. Theoretical calculations are performed based on a realistic tight-binding model for Bi2Se3. We study both three-dimensional devices, which exploit the surface states of Bi2Se3, as well as two-dimensional devices, which exploit the edge states of thin Bi2Se3 strips. We demonstrate that the material properties of Bi2Se3 allow a TMR ratio at room temperature of the order of 1000%. Analytical formulas are derived that allow a quick estimate of the achievable TMR ratio in these devices. The devices can be used to measure the spin polarization of the topological surface states as an alternative to spin ARPES. Unlike TMR devices based on magnetic tunnel junctions the present devices avoid the use of a second ferromagnetic electrode whose magnetization needs to be pinned.

Pure spin current devices based on ferromagnetic topological insulators.

Two-dimensional topological insulators possess two counter propagating edge channels with opposite spin direction. Recent experimental progress allowed to create ferromagnetic topological insulators realizing a quantum anomalous Hall (QAH) state. In the QAH state one of the two edge channels disappears due to the strong ferromagnetic exchange field. We investigate heterostructures of topological insulators and ferromagnetic topological insulators by means of numerical transport calculations. We show that spin current flow in such heterostructures can be controlled with high fidelity. Specifically, we propose spintronic devices that are capable of creating, switching and detecting pure spin currents using the same technology. In these devices electrical currents are directly converted into spin currents, allowing a high conversion efficiency. Energy independent transport properties in combination with large bulk gaps in some topological insulator materials may allow operation even at room temperature.

Appearance of flat surface bands in three-dimensional topological insulators in a ferromagnetic exchange field

We study the properties of the surface states in three-dimensional topological insulators in the presence of a ferromagnetic exchange field. We demonstrate that for layered materials like the surface states on the top surface behave qualitatively different than the surface states at the side surfaces. We show that the group velocity of the surface states can be tuned by the direction and strength of the exchange field. If the exchange field becomes larger than the bulk gap of the material, a phase transition into a topologically nontrivial semimetallic state occurs. In particular, the material becomes a Weyl semimetal, if the exchange field possesses a nonzero component perpendicular to the layers. Associated with the Weyl semimetallic state we show that Fermi arcs appear at the surface. Under certain circumstances either one-dimensional or even two-dimensional surface flat bands can appear. We show that the appearance of these flat bands is related to chiral symmetries of the system and can be understood in terms of topological winding numbers. In contrast to previous systems that have been suggested to possess surface flat bands, the present system has a much larger energy scale, allowing the observation of surface flat bands at room temperature. The flat bands are tunable in the sense that they can be turned on or off by rotation of the ferromagnetic exchange field. Our findings are supported by both numerical results on a finite system as well as approximate analytical results.

Recombinant RNA-Dependent RNA Polymerase Complex of Ebola Virus

Here we report on the expression, purification and characterization of recombinant ebola virus RNA-dependent RNA polymerase (EBOV RdRp). Active protein complexes composed of the large L protein and viral protein VP35 were isolated from insect cells and analyzed using a short primer/template substrate that allowed benchmarking against related enzymes. RNA synthesis by multiprotein complexes of EBOV, influenza B, respiratory syncytial virus (RSV) and monomeric enzymes of hepatitis C and Zika (ZIKV) viruses required a 5′-phosporylated primer. The minimum length of the primer varied between two and three nucleotides in this system. The EBOV enzyme utilizes Mg2+ as a co-factor and the D742A substitution provides an active site mutant that likely affects binding of the catalytic metal ions. Selectivity measurements with nucleotide analogues translate our assay into quantitative terms and facilitate drug discovery efforts. The related EBOV and RSV enzymes are not able to efficiently discriminate against ara-cytidine-5′-triphosphate. We demonstrate that this compound acts like a non-obligate chain-terminator.

Tribute to Mark Wainberg

© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Introduction/preface How do you remember Dr. Mark Wainberg? That is the question we posed to his trainees, former students, post-doctoral fellows and colleagues. Listed below are just a sample of the overwhelming response to this question we received from around the world. Together, Hugo Soudeyns, Anne Gatignol, Andrew Mouland, Matthias Götte, and Chen Liang compiled these tributes and I penned this introduction on behalf of my colleagues.