Presence of JC virus-specific CTL in the cerebrospinal fluid of PML patients: rationale for immune-based therapeutic strategies.
OBJECTIVE
There is urgent need of a treatment for progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). To evaluate the rationale for immunotherapy of PML, we explored whether JCV-specific cytotoxic T lymphocytes (CTL) can penetrate the central nervous system (CNS). In addition, we studied the breadth of their T-cell receptor (TCR) repertoire, and sought to establish a reliable method to expand these cells in vitro.


METHODS
We enrolled 18 patients in this study, including 16 with proven or possible PML (15 HIV-positive and one HIV-negative), and two HIV-positive patients with other neurological diseases. Detection of JCV-specific CTL in the blood and the cerebrospinal fluid was performed by Cr release and tetramer staining assays in 15 patients.


RESULTS
Of 11 PML patients with analyzable cerebrospinal fluid (CSF), two had no detectable JCV-specific CTL in the blood and CSF and died 3.7 and 7.2 months later. The nine remaining patients had an inactive course of PML and detectable JCV-specific CTL in the blood. In addition, four of them (44%) also had detectable JCV-specific CTL in the CSF. Both HIV-positive patients with OND had detectable JCV-specific CTL in the blood and one in the CSF. Using tetramer technology, we obtained highly enriched JCV-specific CTL lines that were able to kill target cells presenting JCV peptides. The breadth of the TCR repertoire was CTL epitope dependent.


CONCLUSIONS
These results indicate that JCV-specific CTL are present in the CNS of PML patients and pave the way for an immune-based therapeutic approach.
Du Pasquier
Renaud A
RA
Division of Viral Pathogenesis and Beth Israel Deaconess Medical Center, Boston Massachusetts 02215, USA.
Autissier
Patrick
P
Zheng
Yue
Y
Jean-Jacques
Jims
J
Koralnik
Igor J
IJ
D000328:Adult; D036022:Capsid Proteins / Q000134:cerebrospinal fluid; D002469:Cell Separation; D018984:Epitopes, T-Lymphocyte / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy; D007577:JC Virus / Q000302:isolation & purification*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000134:cerebrospinal fluid* / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000821:virology*
D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D016693:Receptors, Antigen, T-Cell, alpha-beta; C062481:VP1 protein, polyomavirus