Persistence and pathogenesis of the neurotropic polyomavirus JC.

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.

Co-occurrence of two cases of progressive multifocal leukoencephalopathy in a natalizumab "infusion group".

We observed two cases of progressive multifocal leukoencephalopathy (PML) that occurred in the same "infusion group". The group consisted of four patients with relapsing-remitting multiple sclerosis (RRMS) who had been treated with natalizumab (NAT) in the same medical practice for more than four years at the same times and in the same room, raising concerns about viral transmission between members of the infusion group. DNA amplification and sequence comparison of the non-coding control region (NCCR) of JC virus (JCV) present in cerebrospinal fluid (CSF) samples from PML patients #1 and #2 revealed that the amplified JCV sequences differed from the JCV archetype. The NCRR of the viral DNA was unique to each patient, arguing against the possibility of viral transmission between patients. Statistical considerations predict that similar co-occurrences of PML are likely to happen in the future.

Pathogenesis of progressive multifocal leukoencephalopathy--revisited.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system that is rare even though the proven etiological agent of PML, the polyomavirus JC (JC virus), is ubiquitous within the human population. The common feature of PML cases appears to be underlying immunosuppression, and PML has gained clinical visibility because of its association with human immunodeficiency virus and AIDS and its occurrence as a side effect of certain immunomodulatory drugs. A hypothesis has gained general acceptance that JC virus causes a primary infection in childhood and enters a latent state, after which immunosuppression allows viral reactivation leading to PML. Nonetheless, many important aspects of PML pathogenesis remain unclear, including the molecular bases of latency and reactivation, the site(s) of latency, the relationship of archetype and prototype virus and the mode of virus transmission within the body and between individuals. In this review, we will revisit these areas and examine what the available evidence suggests.

Role of the environment in the transmission of JC virus.

JC virus is etiologically associated with a fatal demyelinating disease known as PML. JCV produces persistent infections in the kidney and is excreted in the urine of healthy individuals and in the urine of PML patients. The characteristics of the JCV excreted in the environment have been studied by analyzing sewage samples from divergent geographical areas. The intergenic region of JCV strains detected in the sewage of Barcelona (Spain), Umeå (Sweden), Nancy (France), Pretoria (South Africa), Patras (Greece), Cairo (Egypt), Washington, D.C. (USA), and diverse areas of Northern India has been sequenced, and the phylogenetic analysis showed their relationships with JCV strains previously described in urine or clinical samples in these geographic areas. The JCV regulatory region of the JCV DNA detected in sewage presented archetypal or archetypal-like regulatory regions with the exception of one of the twenty clones obtained from a sewage sample of the area of Washington, D.C. that presented a tandem repeated structure. Infectivity studies showed that archetypal JCV present in the urine of a pregnant woman productively infected SVG cells. Also JC viral particles showed considerable stability in sewage at 20 degrees C and in front of treatments with acidic pH and trypsin. The high prevalence of JCV in urine and in sewage and the stability of the viral particles observed suggests that contaminated water, food, and fomites could be the vehicles of JCV transmission through the oral route. Virions partially degraded or noninfectious could be a source of JCV DNA and may represent an additional mechanism of entry of viral genes into cells.

Asian genotypes of JC virus in Japanese-Americans suggest familial transmission.

To examine the mode of JC virus (JCV) transmission, we collected urine samples from second- and third-generation Japanese-Americans in Los Angeles, Calif., whose parents and grandparents were all Japanese. From the urine samples of these Japanese-Americans, we mainly detected two subtypes (CY and MY) of JCV that are predominantly found among native Japanese. This finding provides support for the hypothesis that JCV is transmitted mainly within the family through long-term cohabitation.

Excretion and transmission of JCV in human populations.

The potential transmission of JCV through the environment has been analyzed by studying the JC viruses present in raw sewage of urban populations from widely divergent geographical areas. High numbers of JCV were found. JCV was detected in 98% (51/52) of sewage samples from different geographical areas in Europe, Africa, and USA by applying a Nested-PCR procedure. The mean estimated concentration of JCV in sewage was of 10(2)-10(3) viral particles/ml. Sequence analysis shows that JCV found in environmental samples present an archetypal structure in the regulatory region as it has been described in urine samples. Cerebrospinal fluid samples (CSF) of PML (progressive multifocal leucoencephalopathy) patients were also analyzed as control samples in this study presenting tandem repeats and rearrangements at the regulatory region (RR). Sequence analysis of the intergenic region (IGR) allowed the typification and phylogenetic analysis of the JCV sequences detected in sewage. JC viral particles were also found to be stable in sewage samples at 20 degrees C for more than 70 days. This data suggest the idea that the intake of water or food contaminated with JCV could constitute a portal of entry for the virus or the viral DNA to the human organism.