Evidence of the Mechanism by Which Polyomaviruses Exploit the Extracellular Vesicle Delivery System during Infection.

Simone Giannecchini

doi:10.3390/v12060585

Abstract

Increasing evidence suggests that human viruses can hijack extracellular vesicles (EVs) to deliver proteins, mRNAs, microRNAs (miRNAs) and whole viral particles during viral persistence in the host. Human polyomavirus (PyV) miRNAs, which downregulate large T-antigen expression and target host factors, help the virus escape immune elimination and may have roles in the success of viral persistence/replication and the development of diseases. In this context, several investigations have detected PyV miRNAs in EVs obtained from cell culture supernatants after viral infection, demonstrating the ability of these vesicles to deliver miRNAs to uninfected cells, potentially counteracting new viral infection. Additionally, PyV miRNAs have been identified in EVs derived from the biological fluids of clinical samples obtained from patients with or at risk of severe PyV-associated diseases and from asymptomatic control healthy subjects. Interestingly, PyV miRNAs were found to be circulating in blood, urine, cerebrospinal fluid, and saliva samples from patients despite their PyV DNA status. Recently, the association between EVs and PyV viral particles was reported, demonstrating the ability of PyV viral particles to enter the cell without natural receptor-mediated entry and evade antibody-mediated neutralization or to be neutralized at a step different from that of the neutralization of naked whole viral particles. All these data point toward a potential role of the association between PyVs with EVs in viral persistence, suggesting that further work to define the implication of this interaction in viral reactivation is warranted.

Highlights

Polyomaviruses (PyVs) are nonenveloped, small icosahedral viruses whose genomes consist of a single molecule of closed circular, supercoiled, double-stranded DNA
To date, increasing evidence suggests that the use of extracellular vesicles (EVs) as an intercellular communication
To date, increasing evidence suggests that the use ofpersistence

Summary

Introduction

Polyomaviruses (PyVs) are nonenveloped, small icosahedral viruses whose genomes consist of a single molecule of closed circular, supercoiled, double-stranded DNA. Molecular investigations and serological studies have reported that JCPyV and BKPyV, and the less extensively investigated novel PyVs, are ubiquitous and highly prevalent (up to 90% positivity) in the normal human population [6] In this context, primary infections that are asymptomatic in healthy individuals and predominantly occur early in childhood with transmission mainly through an orofecal or respiratory route, are subclinical [6]. Increasing evidence demonstrates that after cell infection, many viruses may hijack secretory extracellular vesicles (EVs) [8] to carry several viral components and, in some instances, infectious viruses, providing additional routes of transmission and escape from immune recognition and facilitating viral persistence in the infected host [9,10,11,12] In this context, investigating the molecular mechanism of the interaction between viruses and infected cells during the late phase of viral replication has been fundamental to elucidating the association of viruses with the EV secretory pathway to discern the role of this mechanism in viral persistence. The published literature on the features of the PyV–EV interaction are reviewed, with a focus on the potential role of this interaction during PyV infection on the ability of PyVs to persist in the host

Polyomavirus Life Cycle and Extracellular Vesicles Biogenesis

Polyomavirus Association with Extracellular Vesicles

Methods

Findings

Concluding Remarks