JC polyomavirus attachment, entry, and trafficking: unlocking the keys to a fatal infection

Abstract

The human JC polyomavirus (JCPyV) causes a lifelong persistent infection in the reno-urinary tract in the majority of the adult population worldwide. In healthy individuals infection is asymptomatic, while in immunocompromised individuals the virus can spread to the central nervous system and cause a fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). There are currently very few treatment options for this rapidly progressing and devastating disease. Understanding the basic biology of JCPyV-host cell interactions is critical for the development of therapeutic strategies to prevent or treat PML. Research in our laboratory has focused on gaining a detailed mechanistic understanding of the initial steps in the JCPyV life cycle in order to define how JCPyV selectively targets cells in the kidney and brain. JCPyV requires sialic acids to attach to host cells and initiate infection, and JCPyV demonstrates specificity for the oligosaccharide lactoseries tetrasaccharide c (LSTc) with an α2,6-linked sialic acid. Following viral attachment, JCPyV entry is facilitated by the 5-hydroxytryptamine (5-HT)2 family of serotonin receptors via clathrin-dependent endocytosis. JCPyV then undergoes retrograde transport to the endoplasmic reticulum (ER) where viral disassembly begins. A novel retrograde transport inhibitor termed Retro-2cycl prevents trafficking of JCPyV to the ER and inhibits both initial virus infection and infectious spread in cell culture. Understanding the molecular mechanisms by which JCPyV establishes infection will open up new avenues for the prevention or treatment of virus-induced disease.

Progressive multifocal leukoencephalopathy and hematologic malignancies: a single cancer center retrospective review

“…Additionally, some pharmacological agents have been suggested based on theoretical or anecdotal evidence that they halt the exit of the virus from an infected cell, or decrease JCV replication. 8,21,22 Prospective clinical studies with cidofovir, cytarabine, mefloquine, and interferon-a have not shown any benefit. 5,6,23 In our patients, the median survival for the 11 patients who received PML-directed treatment was 4.3 months as opposed 0.8 months for those who were not treated; however, this is likely due to patient selection bias based on performance status and other factors, and the longer survival cannot be attributed exclusively to treatment efficacy, which is a major limitation of this retrospective review.…”

Progressive multifocal leukoencephalopathy: current treatment options and future perspectives

“…Both retro-2cycl and brefeldin A were shown to inhibit JCV infection in vitro [Maginnis et al 2014;Nelson et al 2012Nelson et al , 2013, and retro2cycl was also shown to inhibit infectious spread in cultured cells [Maginnis et al 2014].…”

“…Due to lack of tools that could predict the onset and severity of IRIS and because of concerns that a premature and overly aggressive corticosteroid treatment may be counter effective [Antoniol et al 2012], most clinicians withhold corticosteroids until a well-demonstrated IRIS response is identified, and then conservatively titrate the inflammatory response [Clifford, 2014]. [Elphick et al 2004;Maginnis et al 2014;Nelson et al 2012;Atwood, 2001]. Several compounds targeting the serotonin receptor have shown antiviral activity in vitro: chlorpromazine, citalopram, risperidone, ziprasidone, and mirtazapine [Atwood, 2001;Elphick et al 2004].…”

May baseline JCV status influence the MS clinical evolution during Natalizumab treatment? Evidence from a multicenter-2 years-prospective study

“…JC virus (JCV) is a human polyomavirus that, after reactivation in immunocompromised individuals, can cause progressive multifocal leukoencephalopathy (PML) [2]. PML is a fatal demyelinating disease of the white matter of the brain, due to the lytic destruction of oligodendrocytes infected by JCV [3].…”