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Targeting Inside-Out Phosphatidylserine as a Therapeutic Strategy For Viral Diseases

Department of Pharmacology, 6001 Forest Park Road, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
Nature medicine (Impact Factor: 28.05). 12/2008; 14(12):1357-62. DOI: 10.1038/nm.1885
Source: PubMed

ABSTRACT There is a pressing need for antiviral agents that are effective against multiple classes of viruses. Broad specificity might be achieved by targeting phospholipids that are widely expressed on infected host cells or viral envelopes. We reasoned that events occurring during virus replication (for example, cell activation or preapoptotic changes) would trigger the exposure of normally intracellular anionic phospholipids on the outer surface of virus-infected cells. A chimeric antibody, bavituximab, was used to identify and target the exposed anionic phospholipids. Infection of cells with Pichinde virus (a model for Lassa fever virus, a potential bioterrorism agent) led to the exposure of anionic phospholipids. Bavituximab treatment cured overt disease in guinea pigs lethally infected with Pichinde virus. Direct clearance of infectious virus from the blood and antibody-dependent cellular cytotoxicity of virus-infected cells seemed to be the major antiviral mechanisms. Combination therapy with bavituximab and ribavirin was more effective than either drug alone. Bavituximab also bound to cells infected with multiple other viruses and rescued mice with lethal mouse cytomegalovirus infections. Targeting exposed anionic phospholipids with bavituximab seems to be safe and effective. Our study demonstrates that anionic phospholipids on infected host cells and virions may provide a new target for the generation of antiviral agents.

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    • "These results were confirmed by another study that found substitution with a non-biologically relevant isomer of PtdSer restored infectivity (Laliberte and Moss, 2009). In addition, a role for viral envelope PtdSer during infection was demonstrated for Pichinde virus and HIV-1 (Soares et al., 2008; Callahan et al., 2003). A protein complex composed of growth-arrest-specific 6 (Gas6) and the tyrosine kinase receptor, Axl, was the first set of cellular proteins to be implicated in PtdSer-binding enhancement of viral entry (Morizono et al., 2011). "
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    ABSTRACT: A variety of both RNA and DNA viruses envelop their capsids in a lipid bilayer. One of the more recently appreciated benefits this envelope is incorporation of phosphatidylserine (PtdSer). Surface exposure of PtdSer disguises viruses as apoptotic bodies; tricking cells into engulfing virions. This mechanism is termed apoptotic mimicry. Several PtdSer receptors have been identified to enhance virus entry and we have termed this group of proteins PtdSer-mediated virus entry enhancing receptors or PVEERs. These receptors enhance entry of a range of enveloped viruses. Internalization of virions by PVEERs provides a broad mechanism of entry with little investment by the virus itself. PVEERs may allow some viruses to attach to cells, thereby making viral glycoprotein/cellular receptor interactions more probable. Alternatively, other viruses may rely entirely on PVEERs for internalization into endosomes. This review provides an overview of PtdSer receptors that serve as PVEERs and the biology behind virion/PVEER interaction.
    Virology 09/2014; s 468–470:565–580. DOI:10.1016/j.virol.2014.09.009 · 3.28 Impact Factor
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    • "A number of viruses including EBOV have now been shown to utilize PS exposed on the outer membrane envelope of the virus to facilitate entry into target cells (Soares et al., 2008; Jemielity et al., 2013; Morizono and Chen, 2014). PS interacts with the TIM-1 receptor on human cells and inhibition of PS exposure or PS availability to interact with the TIM-1 receptor, may be of great therapeutic value in a number of viral infections (Jemielity et al., 2013; Moller-Tank et al., 2013; Morizono and Chen, 2014). "
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    ABSTRACT: Lipid-enveloped viruses contain a lipid bilayer coat that protects their genome and helps to facilitate entry into the host cell. Filoviruses are lipid-enveloped viruses that have up to 90% clinical fatality and include Marbug (MARV) and Ebola (EBOV). These pleomorphic filamentous viruses enter the host cell through their membrane-embedded glycoprotein and then replicate using just seven genes encoded in their negative-sense RNA genome. EBOV budding occurs from the inner leaflet of the plasma membrane (PM) and is driven by the matrix protein VP40, which is the most abundantly expressed protein of the virus. VP40 expressed in mammalian cells alone can trigger budding of filamentous virus-like particles (VLPs) that are nearly indistinguishable from authentic EBOV. VP40, such as matrix proteins from other viruses, has been shown to bind anionic lipid membranes. However, how VP40 selectively interacts with the inner leaflet of the PM and assembles into a filamentous lipid enveloped particle is mostly unknown. This article describes what is known regarding VP40 membrane interactions and what answers will fill the gaps.
    Frontiers in Microbiology 06/2014; 5:300. DOI:10.3389/fmicb.2014.00300 · 3.94 Impact Factor
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    • "In the case of the Human Immunodeficiency Virus (HIV), phosphatidylserine (PS) and gangliosides (such as GM 1 and GM 3 ) were reported to have functionalities in cell binding, infectivity and trans-infection [2] [3]. The diverse role of viral membrane lipids in disease-relevant processes makes them potential diagnostic and therapeutic targets and motivates the monitoring of their (relative) concentrations [4]. Mass spectrometry (MS) is a valuable tool for quantification of lipids in general. "
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    ABSTRACT: The superior optical properties of gold nanoparticles were used to estimate the concentration of two crucial lipids on virus surface. This is a novel high-throughput and rapid surface characterization approach for viruses in low-concentration samples.
    CLEO: Applications and Technology; 06/2014
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