JC Polyomavirus Attachment and Entry: Potential Sites for PML Therapeutics

Abstract

Purpose of review: JC polyomavirus (JCPyV) is a significant human pathogen that causes an asymptomatic infection in the kidney in the majority of the population. In immunosuppressed individuals, the virus can become reactivated and spread to the brain, causing the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML). There are currently limited treatment options for this fatal disease. Attachment to receptors and entry into host cells are the initiating events in JCPyV infection and therefore an attractive target for therapeutics to prevent or treat PML. This review provides the current understanding of JCPyV attachment and entry events and the potential therapeutics to target these areas.

Recent findings: JCPyV attachment and entry to host cells is mediated by α2,6-linked lactoseries tetrasaccharide c (LSTc) and 5-hydroxytryptamine receptors (5-HT₂Rs), respectively, and subsequent trafficking to the endoplasmic reticulum is required for infection. Recently, vaccines, monoclonal antibodies, and small molecules have shown promise as anti-viral and PML therapies.

Summary: This review summarizes our current understanding of JCPyV attachment, entry, and trafficking and the development of potential PML therapeutics that inhibit these critical steps in JCPyV infection.

Keywords: JC Polyomavirus; Natalizumab; Progressive Multifocal Leukoencephalopathy; Serotonin Receptors; VP1.

Fig. 1. Attachment and entry of JCPyV into host cells and potential targets for PML treatment

JCPyV binds to α2,6 sialic acid-containing receptor lactoseries tetrasaccharide c (LSTc) through interactions with the viral capsid protein VP1 (pentamer in red) to initiate infection of susceptible cells. JCPyV binds with weak affinity to sialic acid-containing gangliosides, however, this interaction does not appear to lead to productive infection. Following interactions with LSTc, JCPyV enters cells through clathrin-mediated endocytosis in an EPS15-dependent manner that is sensitive to chlorpromazine treatment. The serotonin 2 subfamily (5-HT_{2A, 2B, 2C}) of receptors play an important role in viral internalization, yet are not thought to contribute to virus binding. Mirtazapine and chlorpromazine interfere with viral infection, possibly by disrupting JCPyV interactions with serotonin receptors. Following endocytosis, JCPyV likely accumulates in Rab5-positive early endosomes. JCPyV also localizes with Cav-1 positive vesicles, but it is currently unclear whether these are also early endosomes. The virus then undergoes retrograde transport to the ER, a step that is sensitive to Retro-2 treatment.