The curious incident of the dog in the nighttime: does the absence of virus replication in Epstein-Barr virus-transformed B cells point to an important feature of JC virus biology?

The article by Chapagain and Nerurkar [1] in this issue of the Journal reports interesting findings of JC virus (JCV) expression in an Epstein-Barr virus (EBV)– transformed cell line. JCV is the etiologic agent of progressive multifocal leukoen-cephalopathy (PML), a demyelinating disease following the lytic infection of oli-godendrocytes in patients who most often have cellular immune deficiencies, in particular , human immunodeficiency virus infection and/or AIDS [2]. PML follows reactivation of primary infection, which occurs in children and young adults. Progress in defining the sites of JCV latency/ persistence and reactivation over the past 2 decades has led to a better understanding of the pathogenesis of PML. The molecular biology of JCV requires that cells that support virus replication express host cell nuclear transcription factors that recognize the virus regulatory region. Rearrangement and alteration of the virus regulatory region are likely to be additional requirements [3]. The regulatory region controlling virus expression is the most variable portion of the JCV genome. Primary JCV infection occurs with the archetype strain, which has a regulatory region capable of supporting virus expression in uroepithelial cells but is inefficient in most other cell types. JCV isolated from brains of patients with PML and B lym-phocytes have rearranged regulatory sequences , most often with 98–base pair tandem repeats, with and without insertions and deletions, which support virus replication in oligodendrocytes, leading to demyelination. The regulatory regions found in JCV isolated from the brains of patients with PML and B lymphocytes can be theoretically generated from the archetype sequence [4]. The site at which alterations in the archetype regulatory region required for efficient activity in glial and B cells has remained elusive. Once the altered regulatory regions are present, host cells supporting virus reactivation and replication must express nuclear transcription factors (NTFs) that recognize DNA sequences in the altered regulatory region and drive virus expression. The biology of B lymphocyte development and matura-tion suggests they may be an ideal site for these events to occur. Replication of JCV in B lymphocytes was first described in 1988 by S.A.H. [5]. We reported 2 patients with PML, 1 with human immunodeficiency virus infection and AIDS, and the other with no identified underlying disease but who had polyclonal B cell activation, with evidence of JCV infection of B cells. JCV DNA was detected in B lymphocytes in the bone marrow and spleen by in situ hybridization. The viral genome …