Identification of JC virus variants in multiple tissues of pediatric and adult PML patients

Abstract

The transcriptional control region (TCR) of JC virus (JCV), the causative agent of progressive multifocal leukoencephalopathy (PML), undergoes rearrangement during replication of the virus in its human host. The mechanism by which viral promoter/enhancer sequences are deleted and duplicated within the TCR of the archetype form of JCV is not understood, but it is hypothesized that the generation of JCV variants with rearranged TCRs contributes to the virus's pathogenic potential. In a recent study of a pediatric PML patient, we detected extensive rearrangement of the JCV TCR in multiple tissues, and the archetype TCR was amplified from sites other than the kidney. These findings differed from those of previous studies that had examined tissues from adult PML patients. Since exposure to JCV usually occurs early in life, it is likely that some pediatric cases of PML arise as the result of a primary infection, whereas adult cases of PML are thought to result from the reactivation of an infection suffered as an immunocompetent child. To investigate further whether rearrangement of the JCV TCR is affected by the host's age and immune status at the time of exposure, a second pediatric patient and two adult PML patients were examined. As in our first study, multiple tissues were found to contain JCV DNA; however, fewer rearranged variants were detected. In one adult patient, related rearranged variants were detected in the brain, while archetype JCV was found in the other tissues. Based on differences in their VP1 sequences, these two forms represented different JCV genotypes, indicating that this patient had suffered a dual infection. The relevance of these findings to the rearrangement process that alters the JCV TCR is discussed.

The Dynamics of Herpesvirus and Polyomavirus Reactivation and Shedding in Healthy Adults: A 14‐Month Longitudinal Study

“…In the present study, an important finding is that PCR-detected JCV DNA in urine represents an infectious form of the virus, since JCV DNA was detected in COS-7 cells inoculated with urine samples from healthy volunteers. Urinary JCV contained archetypal regulatory regions, a finding that is consistent with the notion that the transmitted form of the virus has this arrangement [28,44,45]. Furthermore, within a given individual, the JCV sequences that were analyzed in multiple samplings over the course of this study remained stable.…”

Human Polyomavirus JC (JCV) Infection of Human B Lymphocytes: A Possible Mechanism for JCV Transmigration across the Blood‐Brain Barrier

“…PCR analyses have demonstrated that JCV may persist in the brain, tonsils and lymphocytes of individuals with and without PML [2, 6-11, 13, 16, 40, 41] and it was proposed that JCV might employ B-lymphocytes to cross the BBB [8, 12, 14-16], similar to HIV and simian immunodeficiency virus (SIV), which gain entry into the brain via infected monocytes (Trojan horse) [42]. Further studies also suggested presence of JCV DNA in the PBMC of 17.4% of 69 HIV-1-positive immunocompetent patients, in 23.2% of 82 HIV-1-positive immunocompromised patients, and in 60% of AIDS patients with PML [43].…”

The role of polyomaviruses in human disease

“…Additionally, endothelial cells have been shown to support BKV replication in vitro , raising the possibility that BKV may cross the endothelial barrier to disseminate from the periphery to its target organs via blood (Hanssen Rinaldo et al, 2005). There are rare reports of JCV sequence detection in various tissues and cells including the liver, lung, spleen, lymph nodes, and colorectal epithelium (Caldarelli-Stefano et al, 1999; Doerries, 2001; Grinnell et al, 1983; Laghi et al, 1999; Newman and Frisque, 1997; Newman and Frisque, 1999). While JCV reactivation leads primarily to infection of the brain, it is unclear whether normal brain tissue harbors the virus (Doerries, 2001).…”