Persistence and pathogenesis of the neurotropic polyomavirus JC

Abstract

Many neurological diseases of the central nervous system (CNS) are underpinned by malfunctions of the immune system, including disorders involving opportunistic infections. Progressive multifocal leukoencephalopathy (PML) is a lethal CNS demyelinating disease caused by the human neurotropic polyomavirus JC (JCV) and is found almost exclusively in individuals with immune disruption, including patients with human immunodeficiency virus/acquired immunodeficiency syndrome, patients receiving therapeutic immunomodulatory monoclonal antibodies to treat conditions such as multiple sclerosis, and transplant recipients. Thus, the public health significance of this disease is high, because of the number of individuals constituting the at-risk population. The incidence of PML is very low, whereas seroprevalence for the virus is high, suggesting infection by the virus is very common, and so it is thought that the virus is restrained but it persists in an asymptomatic state that can only occasionally be disrupted to lead to viral reactivation and PML. When JCV actively replicates in oligodendrocytes and astrocytes of the CNS, it produces cytolysis, leading to formation of demyelinated lesions with devastating consequences. Defining the molecular nature of persistence and events leading to reactivation of the virus to cause PML has proved to be elusive. In this review, we examine the current state of knowledge of the JCV life cycle and mechanisms of pathogenesis. We will discuss the normal course of the JCV life cycle including transmission, primary infection, viremia, and establishment of asymptomatic persistence as well as pathogenic events including migration of the virus to the brain, reactivation from persistence, viral infection, and replication in the glial cells of the CNS and escape from immunosurveillance.

FIGURE 1. Schematic diagram of the occurrence of PML in the US

A Venn diagram is shown illustrating the occurrence of PML (gold circles) in different populations in the US. The outer circle represents the total population of the US, which was 314 million in 2012. The outer black portion represents the vast majority of the population who are immunologically healthy. Note that the group labeled as immunologically healthy refers to individuals with no apparent cause of immunosuppression and includes the elderly, patients with chronic liver or kidney disease and those with idiopathic or transient lymphocytopenia and, as such, could have an occult immunosuppression that is not recognized. The purple circle indicates the subpopulation of people who have impaired cell-mediated immunity (CMI), e.g., cancer survivors, rheumatoid arthritis patients treated with immunosuppressive agents such as rituximab, bone marrow and solid organ transplant recipients, MS patients receiving natalizumab ((https://medinfo.biogenidec.com/), fingolimod : http://www.fda.gov/Drugs/DrugSafety/ucm366529.htm or dimethyl fumarate etc. The inner red circle represents the subpopulation of people with impaired CMI who are infected with HIV-1/AIDS (1.2 million).

FIGURE 2. Schematic diagram of the JCV life cycle and pathogenesis of PML

The events thought to occur during the JCV life cycle and pathogenesis of PML are shown with the common non-pathogenic events labeled in green and the rare pathogenic events in red. Virions in the environment (top right hand corner), which are mainly thought to have an archetypal configuration (blue), but sometimes occasionally the neurotropic form (red), are transmitted through the mouth and nose (1) and enter into the bloodstream through either the epithelium of the tonsils and the upper respiratory tract (2) or the GI tract (3) to establish a primary viremia (4). The nature of the primary viremia is not well understood but current hypotheses are that virus may exist as free virions and/or as white blood cell-associated virus (5). Virus is spread hematogenously to the kidney (6) and other organs. In the kidney, JCV can replicate sporadically and at low levels in the epithelium of the kidney tubules from where it can shed from the apical face of the kidney epithelium leading to viruria and transmission of virions into the environment in the urine (7) completing the normal JCV life cycle. Virus may spread to the bone marrow (8), where it has been postulated but is not proven that neurotropic virus (red) may emerge by an unknown mechanism. Subsequently, JCV may undergo hematogenous spread from the bone marrow and possibly other locations in association with leukocytes (9) to other sites including the brain (10) where neurotropic JCV DNA can be detected in healthy, immunocompetent individuals in the absence of expression of detectable levels of viral proteins. Under conditions of immunosuppression, neurotropic JCV can become reactivated and undergoes transcription, DNA replication and spreads to form microlesions, which can coalesce, increase in size and result in PML. The pathological features of PML are shown in the bottom panels and are (from left to right): T2-weighted magnetic resonance image of the brain showing hyperintense signal abnormalities in the white matter of the parieto-occipital lobes due to PML; hematoxylin and eosin staining of a PML tissue section for lipids showing demyelination; hematoxylin and eosin staining revealing oligodendrocytes bearing nuclear inclusion bodies (upper arrow) and bizarre astrocytes (lower arrow); electron microscopy of PML tissue showing crystalline arrays of 45 nm viral particles within a nuclear inclusion body.