Journal Article

A Retrograde Trafficking Inhibitor of Ricin and Shiga-Like Toxins Inhibits Infection of Cells by Human and Monkey Polyomaviruses

Williard, Paul, O’Hara, Bethany, Carney, Dan W., Gee, Gretchen V., DiMaio, Daniel, Sello, Jason K., Derdowski, Aaron, Nelson, Christian D. S., Lipovsky, Alex, Atwood, Walter J.

2013

Overview

Polyomaviruses are ubiquitous pathogens that cause severe disease in immunocompromised individuals. JC polyomavirus (JCPyV) is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), whereas BK polyomavirus (BKPyV) causes polyomavirus-induced nephropathy and hemorrhagic cystitis. Vaccines or antiviral therapies targeting these viruses do not exist, and treatments focus on reducing the underlying causes of immunosuppression. We demonstrate that retro-2 cycl , an inhibitor of ricin and Shiga-like toxins (SLTs), inhibits infection by JCPyV, BKPyV, and simian virus 40. Retro-2 cycl inhibits retrograde transport of polyomaviruses to the endoplasmic reticulum, a step necessary for productive infection. Retro-2 cycl likely inhibits polyomaviruses in a way similar to its ricin and SLT inhibition, suggesting an overlap in the cellular host factors used by bacterial toxins and polyomaviruses. This work establishes retro-2 cycl as a potential antiviral therapy that broadly inhibits polyomaviruses and possibly other pathogens that use retrograde trafficking. IMPORTANCE The human polyomaviruses JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) cause rare but severe diseases in individuals with reduced immune function. During immunosuppression, JCPyV disseminates from the kidney to the central nervous system and destroys oligodendrocytes, resulting in the fatal disease progressive multifocal leukoencephalopathy. Kidney transplant recipients are at increased risk of BKPyV-induced nephropathy, which results in kidney necrosis and loss of the transplanted organ. There are currently no effective therapies for JCPyV and BKPyV. We show that a small molecule named retro-2 cycl protects cells from infection with JCPyV and BKPyV by inhibiting intracellular viral transport. Retro-2 cycl treatment reduces viral spreading in already established infections and may therefore be able to control infection in affected patients. Further optimization of retro-2 cycl may result in the development of an effective antiviral therapy directed toward pathogens that use retrograde trafficking to infect their hosts. The human polyomaviruses JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) cause rare but severe diseases in individuals with reduced immune function. During immunosuppression, JCPyV disseminates from the kidney to the central nervous system and destroys oligodendrocytes, resulting in the fatal disease progressive multifocal leukoencephalopathy. Kidney transplant recipients are at increased risk of BKPyV-induced nephropathy, which results in kidney necrosis and loss of the transplanted organ. There are currently no effective therapies for JCPyV and BKPyV. We show that a small molecule named retro-2 cycl protects cells from infection with JCPyV and BKPyV by inhibiting intracellular viral transport. Retro-2 cycl treatment reduces viral spreading in already established infections and may therefore be able to control infection in affected patients. Further optimization of retro-2 cycl may result in the development of an effective antiviral therapy directed toward pathogens that use retrograde trafficking to infect their hosts.

• Publisher: American Society for Microbiology,American Society of Microbiology
• Subject: Adenoviruses / Animals / Antiviral agents / Antiviral Agents - metabolism / Benzamides - metabolism / BK Virus - drug effects / BK Virus - physiology / Cell Line / Central nervous system / cystitis / Demyelinating diseases / Demyelination / Endoplasmic reticulum / Haplorhini / Hemorrhagic cystitis / hosts / Human polyomavirus 1 / Human polyomavirus 2 / Humans / Immune response / immunocompromised population / Immunosuppression / Infections / JC Virus - drug effects / JC Virus - physiology / kidney diseases / kidney transplant / Kidney transplantation / kidneys / Leukoencephalopathy / Macaca mulatta polyomavirus 1 / monkeys / necrosis / Nephropathy / Oligodendrocytes / Pathogens / Progressive multifocal leukoencephalopathy / Protein Transport - drug effects / Retrograde transport / Ricin / Ricin - antagonists & inhibitors / risk / Shiga Toxins - antagonists & inhibitors / Shiga-like toxin / Shiga-like toxins / Simian virus 40 - drug effects / Simian virus 40 - physiology / Thiophenes - metabolism / Toxins / Transplants & implants / Virus Internalization - drug effects / Viruses