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Targeting inside-out phosphatidylserine as a therapeutic strategy for viral diseases

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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Figure 1: Bavituximab binds Pichinde virus–infected cells and infectious virions.
Figure 2: Therapeutic effect against Pichinde virus in lethally infected guinea pigs displaying overt signs of disease.
Figure 3: Mechanism of anti-viral effects of bavituximab.
Figure 4: Broad-spectrum recognition of virus-infected cells and protection against cytomegalovirus infection in mice.

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Acknowledgements

Rabbit Pichinde-specific antiserum was a gift from J. Aronson, University of Texas Medical Branch, Galveston. This work was supported by a US National Institutes of Health grant (5 U01 AI1056412) and a sponsored research agreement with Peregrine Pharmaceuticals. We thank G. Barbero, S. Mims, H. Arizpe, L. Ingram, S. Syed, L. Watkins, S. Li and J. Iglehart for technical assistance. We also thank W. Bresnahan, S. Ran, O. Ramilo, H. Jafri, S. Fussey, M. Roth and J. Albanesi for discussions and comments on the manuscript.

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Contributions

M.M.S. designed and supervised experiments, interpreted results and wrote the manuscript. S.W.K. provided reagents and contributed to experimental design and interpretation of results. P.E.T. conceived the idea of phosphatidylserine-directed antiviral therapy, oversaw experiments and wrote the manuscript.

Corresponding author

Correspondence to Philip E Thorpe.

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Competing interests

M.M.S. holds Peregrine Pharmaceuticals Inc. stock, S.W.K. is employed by Peregrine Pharmaceuticals, and P.E.T. is a consultant, stock holder and has sponsored a research agreement with Peregrine Pharmaceuticals. The company is commercially developing bavituximab for the treatment of virus infections.

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Soares, M., King, S. & Thorpe, P. Targeting inside-out phosphatidylserine as a therapeutic strategy for viral diseases. Nat Med 14, 1357–1362 (2008). https://doi.org/10.1038/nm.1885

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