Polyomavirus JC in the Context of Immunosuppression: A Series of Adaptive, DNA Replication-Driven Recombination Events in the Development of Progressive Multifocal Leukoencephalopathy

Edward M Johnson,Patric S Lundberg,Dianne C Daniel,Margaret J Wortman,Ayuna V Dagdanova

doi:10.1155/2013/197807

Edward M Johnson, Patric S Lundberg + Show 3 more

Open Access

https://doi.org/10.1155/2013/197807

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Abstract

Polyomavirus JC (JCV) is the etiological agent of progressive multifocal leukoencephalopathy (PML), a demyelinating infection of oligodendrocytes in the brain. PML, a frequently fatal opportunistic infection in AIDS, has also emerged as a consequence of treatment with several new immunosuppressive therapeutic agents. Although nearly 80% of adults are seropositive, JCV attains an ability to infect glial cells in only a minority of people. Data suggest that JCV undergoes sequence alterations that accompany this ability, and these changes can be derived from an archetype strain by mutation, deletion, and duplication. While the introductory source and primary tissue reservoir of JCV remain unknown, lymphoid cells have been identified as potential intermediaries in progression of JCV to the brain. This review is focused on sequence changes in the noncoding control region (NCCR) of the virus. We propose an adaptive mechanism that involves a sequential series of DNA replication-driven NCCR recombination events involving stalled DNA replication forks at NCCR palindromic secondary structures. We shall describe how the NCCR sequence changes point to a model in which viral DNA replication drives NCCR recombination, allowing JCV adaptation to different cell types in its progression to neurovirulence.

Highlights

JC virus is well known to reside in the urinary tracts, and possibly other organs, of 50–60% of adults, where it generally is asymptomatic, it may cause a local infection that is not significantly associated with morbidity in immunocompetent individuals [1,2,3,4]
There is a distinct pattern to changes detected in the noncoding control region (NCCR) region of JC virus (JCV) infecting cells in the urinary tract and those infecting cells in the CNS in progressive multifocal leukoencephalopathy (PML)
The NCCR is defined as the DNA sequence between the ATG initiating coding of large Tantigen and that initiating coding of a prospective viral agnoprotein

Summary

Introduction

JC virus is well known to reside in the urinary tracts, and possibly other organs, of 50–60% of adults, where it generally is asymptomatic, it may cause a local infection that is not significantly associated with morbidity in immunocompetent individuals [1,2,3,4]. We shall describe how these changes point to a model in which viral DNA replication drives NCCR recombination allowing JCV to adapt to the replicative environment of different cell types in its progression to neurovirulence. These characteristics are both important for changes in the JCV NCCR that would promote adaptation to replicate in different cell types, including glial cells of the brain.

Results

Conclusion