A Broad-Spectrum Antiviral Peptide Blocks Infection of Viruses by Binding to Phosphatidylserine in the Viral Envelope.

The ongoing threat of viral infections and the emergence of antiviral drug resistance warrants a ceaseless search for new antiviral compounds. Broadly-inhibiting compounds that act on elements shared by many viruses are promising antiviral candidates. Here, we identify a peptide derived from the cowpox virus protein CPXV012 as a broad-spectrum antiviral peptide. We found that CPXV012 peptide hampers infection by a multitude of clinically and economically important enveloped viruses, including poxviruses, herpes simplex virus-1, hepatitis B virus, HIV-1, and Rift Valley fever virus. Infections with non-enveloped viruses such as Coxsackie B3 virus and adenovirus are not affected. The results furthermore suggest that viral particles are neutralized by direct interactions with CPXV012 peptide and that this cationic peptide may specifically bind to and disrupt membranes composed of the anionic phospholipid phosphatidylserine, an important component of many viral membranes. The combined results strongly suggest that CPXV012 peptide inhibits virus infections by direct interactions with phosphatidylserine in the viral envelope. These results reiterate the potential of cationic peptides as broadly-acting virus inhibitors.

A Genome-Wide Haploid Genetic Screen Identifies Heparan Sulfate-Associated Genes and the Macropinocytosis Modulator TMED10 as Factors Supporting Vaccinia Virus Infection.

Vaccinia virus is a promising viral vaccine and gene delivery candidate and has historically been used as a model to study poxvirus-host cell interactions. We employed a genome-wide insertional mutagenesis approach in human haploid cells to identify host factors crucial for vaccinia virus infection. A library of mutagenized HAP1 cells was exposed to modified vaccinia virus Ankara (MVA). Deep-sequencing analysis of virus-resistant cells identified host factors involved in heparan sulfate synthesis, Golgi organization, and vesicular protein trafficking. We validated EXT1, TM9SF2, and TMED10 (TMP21/p23/p24δ) as important host factors for vaccinia virus infection. The critical roles of EXT1 in heparan sulfate synthesis and vaccinia virus infection were confirmed. TM9SF2 was validated as a player mediating heparan sulfate expression, explaining its contribution to vaccinia virus infection. In addition, TMED10 was found to be crucial for virus-induced plasma membrane blebbing and phosphatidylserine-induced macropinocytosis, presumably by regulating the cell surface expression of the TAM receptor Axl.IMPORTANCE Poxviruses are large DNA viruses that can infect a wide range of host species. A number of these viruses are clinically important to humans, including variola virus (smallpox) and vaccinia virus. Since the eradication of smallpox, zoonotic infections with monkeypox virus and cowpox virus are emerging. Additionally, poxviruses can be engineered to specifically target cancer cells and are used as a vaccine vector against tuberculosis, influenza, and coronaviruses. Poxviruses rely on host factors for most stages of their life cycle, including attachment to the cell and entry. These host factors are crucial for virus infectivity and host cell tropism. We used a genome-wide knockout library of host cells to identify host factors necessary for vaccinia virus infection. We confirm a dominant role for heparin sulfate in mediating virus attachment. Additionally, we show that TMED10, previously not implicated in virus infections, facilitates virus uptake by modulating the cellular response to phosphatidylserine.

Microsurgical Treatment of Sporadic and von Hippel-Lindau Disease Associated Spinal Hemangioblastomas: A Single-Institution Experience.

STUDY DESIGN: Retrospective cohort study. PURPOSE: To examine the clinical profile and surgical complications in patients with spinal hemangioblastomas and to evaluate the long-term outcome in them. OVERVIEW OF LITERATURE: Although considered to be histologically benign, hemangioblastomas may cause significant neurological deficits. The proportion of spinal hemangioblastomas associated with von Hippel-Lindau (VHL) disease has been estimated be 13%-59%. Preoperative neurological function correlates with postoperative neurological status. Studies have shown no difference in outcomes between sporadic and VHL-associated spinal hemangioblastomas. METHODS: This retrospective study included 14 consecutive patients treated for spinal hemangioblastomas at our institute between January 2000 and June 2013. The mean follow-up period was 5 years. Magnetic resonance imaging of the complete neuraxis was performed in all cases, and preoperative embolization was performed in two cases. RESULTS: In total, 14 patients underwent 18 surgeries, of which 15 were for spinal hemangioblastomas. Of all the patients, 86% had motor weakness and 79% presented with sensory disturbances. Preoperative McCormick functional grades were grade I in 7 (50%), grade II in 3 (21%), and grade III in 4 (29%) patients; 50% patients were diagnosed with VHL disease. All patients underwent complete resection of the tumor. Eight patients experienced deterioration in their neurological status in the immediate postoperative period; among them, five had gradual improvement. At 5-year follow-up, 11 (78.57%) patients showed good functional outcomes. CONCLUSIONS: Microsurgical excision of spinal hemangioblastomas can cause postoperative morbidity, mainly in the form of neurological deterioration. Almost half of our patients had deterioration in the McCormick grade in the immediate postoperative period. However, a complete microsurgical excision can result in good long-term functional outcomes, as most of the immediate postoperative neurological deterioration in our patients was reversible. There was no difference in the long-term functional outcomes between sporadic and VHL-associated spinal hemangioblastomas.