Person:

Dang, Xin

Infection of glial cells by the human polyomavirus JC (JCV) causes progressive multifocal leukoencephalopathy (PML). JCV Encephalopathy (JCVE) is a newly identified disease characterized by JCV infection of cortical pyramidal neurons. The virus JCVCPN associated with JCVE contains a unique 143 base pair deletion in the agnogene. Contrary to most JCV brain isolates, JCVCPN has an archetype-like regulatory region (RR) usually found in kidney strains. This provided us with the unique opportunity to determine for the first time how each of these regions contributed to the phenotype of JCVCPN. We characterized the replication of JCVCPN compared to the prototype virus JCVMad-1 in kidney, glial and neuronal cell lines. We found that JCVCPN is capable of replicating viral DNA in all cell lines tested, but is unable to establish persistent infection seen with JCVMad-1. JCVCPN does not have an increased ability to replicate in the neuronal cell line tested. To determine whether this phenotype results from the archetype-like RR or the agnogene deletion, we generated chimeric viruses between JCVCPN of JCVMad-1. We found that the deletion in the agnogene is the predominant cause of the inability of the virus to maintain a persistent infection, with the introduction of a full length agnogene, either with or without agnoprotein expression, rescues the replication of JCVCPN. Studying this naturally occurring pathogenic variant of JCV provides a valuable tool for understanding the functions of the agnogene and RR form in JCV replication.

Objective: To describe the compassionate use of interleukin-7 (IL-7) for treatment of progressive multifocal leukoencephalopathy (PML) in the setting of idiopathic CD8+ greater than CD4+ lymphocytopenia. Methods: A 66-year-old HIV-seronegative man presented with progressive language dysfunction. MRI showed hyperintense lesions in the left hemispheric white matter with mild contrast enhancement. A brain biopsy performed 4 months after symptom onset established the diagnosis of PML. The patient had profound lymphocytopenia with absolute lymphocyte count (ALC) at 168 cells/μL, 87 CD4+ T cells/μL, and 7 CD8+ T cells/μL. There was no evidence of hematologic malignancy or rheumatologic disease. Results: The patient received 3 intramuscular injections of IL-7 at a dose of 10 μg/kg per week with no adverse effects. ALC peaked at 595 cells/μL, CD4+ T cells at 301 cells/μL, and CD8+ T cells at 34 cells/μL 3 weeks after completion of treatment. His lesions on MRI stabilized and neurologic examination mildly improved. JCV-specific T-cell responses measured by intracellular cytokine staining were not altered after treatment with IL-7 but there was a marked increase in regulatory T cells. Conclusion: This case further supports the investigational use of IL-7 in patients who develop PML in the setting of ICL. Classification of evidence: This study provides Class IV evidence that for patients with ICL and PML, IL-7 improves PML-related-outcomes. The study is rated Class IV because it is a case report.