Vaccinia Virus
Vaccinia virus produces proteins that either antagonize kinases or bind to adaptor proteins in TLR signaling pathways, suppressing the activation of host cell transcription needed for antiviral responses.
From: Primer to the Immune Response (Second Edition), 2014
The Lister Strain of Vaccinia Virus as an Anticancer Therapeutic Agent
Jahangir Ahmed, ... Yaohe Wang, in Gene Therapy of Cancer (Third Edition), 2014
Introduction
Vaccinia virus (VV) has played a prominent role in one of the greatest achievements in medical history—the eradication of smallpox(caused by variola virus). This occurred in the late 1970s, having claimed the lives of half a billion people worldwide in the preceding three centuries [1]. In 1776, Jenner famously inoculated a small boy with pus obtained from a pustule on the hand of a milkmaid [2]. The active therapeutic responsible for the resulting immunity to smallpox was most likely cowpox virus, which is closely related to but taxonomically different from VV [3]. The origin of VV remains obscure, but by the early 20th century it became the foremost smallpox vaccine [3,4].
Although variola is no longer present in any population, threats of bioterrorism from laboratory-preserved derivatives maintain the potential need for rapid widespread vaccination. Vaccine development thus still remains active. In addition, VV has found utility in other roles, including the immunotherapeutic prevention of other infectious diseases [5] as well as in the treatment of cancer [6]. With regard to the latter, the earliest studies (which mainly used replication-attenuated VV recombinants for fear of toxicity) were relatively disappointing in the clinic. Replication-competent VVs retain their ability to lyse tumor cells and spread through tumor tissue. Recent advances in DNA recombinant technology (enabling the rational manipulation of the viral backbone), coupled with the ever-increasing knowledge gains in the fields of molecular virology and cancer cell biology, have aided the development of safe and efficacious replication-competent oncolytic VVs. These are currently at the forefront of the most promising novel anticancer agents.
Different VV strains were used in different areas of the world for mass vaccination. The anticancer potential of the Lister strain (VVL), which was popular in Europe, is the main focus of this chapter.
Poxviruses
G.L. Smith, ... M.A. Skinner, in Encyclopedia of Virology (Third Edition), 2008
Entry
VACV forms two distinct virion types (IMV and EEV), which are surrounded by different numbers of membranes. These different virions are also produced by viruses from several chordopoxvirus genera, and may be universal for poxviruses. IMV enters by fusion of its membrane with either the plasma membrane or the membrane of an intracellular vesicle following endocytosis. EEV entry is complicated by the second membrane that is shed on contact with the cell by a ligand-dependent nonfusogenic process. This places the IMV from within the EEV envelope against the plasma membrane and thereafter entry takes place as for free IMV. A remarkable feature of VACV fusion is the presence of a complex of nine proteins that are all required for fusion but not binding to the cell. In contrast, the fusion machinery of other enveloped viruses is often only a single protein. The fusion proteins of VACV are conserved in many other poxviruses, suggesting a common mechanism of entry. After a virus core has entered the cell, it is transported on microtubules deeper into the cell (see Figure 2(d) for an image of a virus core).
Virus Assembly and Exit Pathways
Nicolas Cifuentes-Munoz, ... Rebecca Ellis Dutch, in Advances in Virus Research, 2020
2.2 Formation of actin tails
Vaccinia virus (VACV) replication occurs in cytosolic factories, and involves the formation of two forms of infectious virus, the intracellular mature virus (IMV) and extracellular enveloped virus (EEV) (Fig. 1). These two forms differ not only antigenically and structurally, but also in the way they exit the cell (Smith and Law, 2004). The majority of IMV particles are released from cells after lysis. Late in infection, IMV particles can also exit the cell through budding, but the significance of this mechanism is not completely understood. Budding from the plasma membrane, together with exocytosis, are the proposed ways that EEV exits cells. However, an important role of the actin cytoskeleton in VACV assembly was identified after early observations using high-voltage electron microscopy (Stokes, 1976). In infected cells, microvilli containing enveloped VACV particles at their tips were observed at the cell periphery (Stokes, 1976). The formation of the microvilli was shown to be sensitive to cytochalasin B but not to nocodazole, suggesting actin polymerization could play a role in their stabilization. The term actin tails was proposed for VACV-induced microvilli, due to their resemblance to actin tails formed in bacterial infections with Listeria, Shigella or Rickettsia (Cudmore et al., 1995; Welch and Way, 2013). Actin tails are initially observed at the interior of the cell, but as the infection progresses they project from the cell surface up to 20 μm. Enveloped virions located at the tip of actin tails were shown to project toward uninfected cells for direct cell-to-cell spread (Fig. 1) (Cudmore et al., 1995). Soon after the discovery of actin tails, it was demonstrated that phosphorylation of the viral protein A36R by Src and Abl family kinases was essential for the actin-based motility of vaccinia (Frischknecht et al., 1999a,b; Newsome et al., 2006). Phosphorylated A36R recruits the adaptor proteins Nck and Grb2 and the downstream effector N-WASP (Wiscott-Aldrich syndrome protein) together with the WASP Interacting Protein (WIP) (Donnelly et al., 2013; Frischknecht et al., 1999b; Scaplehorn et al., 2002). N-WASP can stimulate the actin-nucleating activity of the Arp2/3 complex (Taylor et al., 2011). In addition, activation of the formin FHOD1 by the small GTPase Rac1 was shown to stimulate vaccinia virus-induced actin tail initiation and elongation, a mechanism independent of the N-WASP-Arp2/3 pathway (Alvarez and Agaisse, 2013) (Fig. 1). Two isoforms of cytoplasmic actin, β and γ-actin, are present in actin tails, but only β-actin was found to be involved in actin nucleation induced by VACV (Marzook et al., 2017). Therefore, the signaling pathway initiated through phosphorylation of VACV A36R to induce actin tail formation for direct cell-to-cell spread was found to be an elegant mimic of cellular pathways. More recently, it was shown that two VACV proteins, A33 and A36, are necessary and sufficient to induce actin tail formation. The early expression of both proteins was shown to be crucial for rapid spread and repulsion of virions to neighboring uninfected cells (Doceul et al., 2010). Additional cellular factors such as clathrin and the clathrin adaptor protein AP-2 enhance actin-based motility of vaccinia. Clathrin and AP-2 are recruited by the extracellular virus during its egress to promote clustering of A36, thus potentiating actin-based motility and spread of the infection (Humphries et al., 2012). Casein kinase 2 (CK2) also enhances actin tail formation of vaccinia virus, potentially through direct phosphorylation of A36 and the recruitment of phosphorylated Src (Alvarez and Agaisse, 2012). Though actin tail formation has been explored in detail for vaccinia virus, the sequence homology of key viral proteins and additional evidence suggest that actin tail formation is a common strategy for orthopoxviruses (Duncan et al., 2018; Newsome and Marzook, 2015; Reeves et al., 2011; Welch and Way, 2013).
Fig. 1. Formation of actin tails. Vaccinia virus (VACV) can spread from cell-to-cell through different mechanisms. In VACV infected cells, intracellular enveloped particles are transported to budding sites, where the outer viral membrane fuses with the plasma membrane (A). Extracellular enveloped viral particles remain attached to the plasma membrane and several cellular factors are recruited to the site through a cascade of events initiated by phosphorylation of the A36R protein cytosolic tail (B). Polymerization of F-actin underneath the plasma membrane occurs through activation of the cellular pathways N-WASP/Arp2/3 and FHOD1/Rac1, leading to elongation of actin tails (C). Viral particles can thus reach adjacent cells for rapid direct cell-to-cell spread.
https://www.sciencedirect.com/topics/medicine-and-dentistry/vaccinia-virus
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