Detection of JC Virus DNA and Proteins in the Bone Marrow of HIV‐Positive and HIV‐Negative Patients: Implications for Viral Latency and Neurotropic Transformation

Abstract

Background We sought to determine the prevalence of JCV in bone marrow samples from HIV-positive and HIV-negative patients and whether the bone marrow is a site of latency and neurotropic transformation of JC virus, the agent of progressive multifocal leukoencephalopathy(PML). Methods We collected bone marrow aspirates, archival bone marrow, blood, and urine samples from 75 HIV-negative and 47 HIV-positive patients without PML, as well as bone marrow, and urine or kidney samples from 8 HIV-negative and 15 HIV-positive patients with PML. Samples were tested for JCV DNA by quantitative PCR and JCV protein expression by immunohistochemistry. JCV regulatory regions (RR) were characterized by sequencing. Results JCV DNA was detected in bone marrow specimens of 10/75(13%) of HIV-negative, and 22/47 (47%) of HIV-positive patients without PML, but in 3/8(38%) HIV-negative and 4/15(27%) HIV-positive patients with PML. JCV DNA(2-1081 cps/μg cellular DNA) was detected in multiple leukocyte subpopulations of blood and bone marrow samples. JCV large T antigen, but not VP1 capsid protein, was expressed in bone marrow plasma cells. Bone marrow JCV RR sequences were similar to those usually found in brain of PML patients. Conclusions The bone marrow is an important reservoir and possible site of neurotropic transformation for JCV.

Natalizumab treatment perturbs memory‐ and marginal zone‐like B‐cell homing in secondary lymphoid organs in multiple sclerosis

“…1 haematopoietic progenitor cells from natalizumab-treated MS patients [23,24]. Furthermore, a putative role of B cells in JCV reactivation and transmigration across the blood-brain barrier has been suggested [25][26][27].…”

“…PML occurs in acquired or constitutive states of immunodeficiency, and in natalizumab-treated MS patients it has been assumed that PML may develop due to compromised immune surveillance of the CNS, although natalizumab may also contribute to PML development by influencing JCV dissemination [18]. Hematopoietic precursor cells and B cells [19][20][21], which are augmented in the peripheral blood of natalizumab-treated patients from the above reasons, have been identified to be susceptible to JCV infection [22], although viral DNA has not been detected in CD341 haematopoietic progenitor cells from natalizumab-treated MS patients [23,24]. Furthermore, a putative role of B cells in JCV reactivation and transmigration across the blood-brain barrier has been suggested [25][26][27].…”

JC Virus Latency in the Brain and Extraneural Organs of Patients with and without Progressive Multifocal Leukoencephalopathy

“…JCV remains latent in the kidneys, lymph nodes, and bone marrow of healthy and immunosuppressed individuals without PML (2,21,24) and, upon reactivation, can cause a lytic infection of oligodendrocytes in the brain, leading to PML (14). Although JCV is often found in the urine of healthy individuals (12,18), it is not usually detected in the blood of patients without PML (15).…”

Atypical Progressive Multifocal Leukoencephalopathy in a Patient with Antisynthetase Syndrome

“…The virus causes symptoms in patients with severe immunodeficiency (AIDS, autoimmune diseases and hematologic neoplasms) (18,19). An analysis of 9,675 patients with PML revealed 0.44% of the cases to involve patients with systemic lupus erythematosus, 0.25% rheumatoid arthritis and 0.06% other connective tissue diseases (20).…”