A Prospective Study Demonstrates an Association Between JC Virus-Specific Cytotoxic T Lymphocytes and the Early Control of Progressive Multifocal Leukoencephalopathy

ABSTRACT JC virus (JCV)-specific cytotoxic T lymphocytes (CTL) in peripheral blood are associated with a favorable outcome in patients with progressive multifocal leukoencephalopathy (PML). However, the frequency of these cells in the peripheral blood mononuclear cells (PBMC) of PML patients is unknown. To develop a highly sensitive assay for detecting the cellular immune response against this virus, we performed a CTL epitope mapping study of JCV VP1 major capsid protein by using overlapping peptides. A novel HLA-A*0201-restricted epitope, the VP1p36 peptide SITEVECFL, was characterized. The cellular immune response against JCV was assessed in 32 study subjects. By combining the results of the 51Cr release assay on pooled peptides and staining with the HLA-A*0201/JCV VP1p36 tetramer, VP1-specific CTL were detected in 10 of 11 PML survivors (91%) versus only 1 of 11 PML progressors (9%, P = 0.0003). VP1-specific CTL were also detected in two of two patients recently diagnosed with PML and in four of four human immunodeficiency virus-positive patients with possible PML. The frequency of CTL specific for the novel VP1p36 and the previously described VP1p100 epitopes was determined. In two patients, the frequency of CTL specific for the VP1p36 or VP1p100 epitopes, as determined by fresh blood tetramer staining (FBTS), ranged from 1/6,000 to 1/24,000 PBMC. A CTL sorting technique combining tetramer staining and selection with immunomagnetic beads allowed the detection of epitope-specific CTL in two cases that were determined to be negative by FBTS. The phenotype of these CTL in vivo was consistent with activated memory cells. These data suggest that, although present in low numbers, JCV-specific CTL may be of central importance in the containment of JCV spread in immunosuppressed individuals.

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JC Virus-Specific Cytotoxic T Lymphocytes in Individuals with Progressive Multifocal Leukoencephalopathy

Journal of Virology ◽

10.1128/jvi.75.7.3483-3487.2001 ◽

2001 ◽

Vol 75 (7) ◽

pp. 3483-3487 ◽

Cited By ~ 86

Author(s):

Igor J. Koralnik ◽

Renaud A. Du Pasquier ◽

Norman L. Letvin

Keyword(s):

Immune Response ◽

T Lymphocytes ◽

Progressive Multifocal Leukoencephalopathy ◽

Cytotoxic T Lymphocytes ◽

Mononuclear Cells ◽

Demyelinating Disease ◽

Jc Virus ◽

Regulatory Protein ◽

Fatal Outcome ◽

Cellular Immune

ABSTRACT Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by a reactivation of the polyomavirus JC (JCV) within a setting of immunosuppression. The nature of the immune response that contains replication of this virus is unknown. We have explored JCV-specific cellular immune responses in patients with PML and control subjects. JCV antigen-stimulated peripheral blood mononuclear cells (PBMC) of four human immunodeficiency virus (HIV)-infected patients who were survivors of PML and one HIV-uninfected patient recently diagnosed with PML lysed autologous B-lymphoblastoid cell lines expressing either the JCV T regulatory protein or the VP1 major capsid protein. This lysis was mediated by CD8+ T lymphocytes and was major histocompatibility complex class I restricted. These cells were therefore cytotoxic T lymphocytes (CTL). JCV-specific CTL could not be detected in PBMC of three HIV-infected PML patients who had progressive neurologic disease and an eventual fatal outcome. These data suggest that the JCV-specific cellular immune response may play a crucial role in the containment of PML. This finding may also prove useful as a favorable prognostic marker in the clinical management of these patients.

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Relationship Between Radiation-Induced Apoptosis of T Lymphocytes and Chronic Toxicity in Patients With Prostate Cancer Treated by Radiation Therapy: A Prospective Study

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2014.01.002 ◽

2014 ◽

Vol 88 (5) ◽

pp. 1057-1063 ◽

Cited By ~ 24

Author(s):

Palmira Foro ◽

Manuel Algara ◽

Joan Lozano ◽

Nuria Rodriguez ◽

Xavier Sanz ◽

...

Keyword(s):

Prostate Cancer ◽

Radiation Therapy ◽

T Lymphocytes ◽

Prospective Study ◽

Chronic Toxicity ◽

Radiation Induced ◽

Induced Apoptosis ◽

A Prospective Study

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Increase in CD3+ CD4- T lymphocytes in patients with AIDS and disseminated Mycobacterium avium-intracellulare complex infection: a prospective study

Microbes and Infection ◽

10.1016/s1286-4579(99)80079-3 ◽

1999 ◽

Vol 1 (10) ◽

pp. 771-776 ◽

Cited By ~ 1

Author(s):

Fabrice Bonnet ◽

Laurence Dequae-Merchadou ◽

Jean-Luc Taupin ◽

Stéphane Sire ◽

Michel Dupon ◽

...

Keyword(s):

T Lymphocytes ◽

Prospective Study ◽

Mycobacterium Avium ◽

Mycobacterium Avium Intracellulare ◽

A Prospective Study

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T Lymphocytes Subsets in CAPD and Hemodialysis (HD) Patients: A Prospective Study

Frontiers in Peritoneal Dialysis ◽

10.1007/978-3-662-11784-2_114 ◽

1986 ◽

pp. 597-599

Author(s):

F. Collart ◽

C. Tielemans ◽

R. Wens ◽

L. Schandene ◽

J. Wybran ◽

...

Keyword(s):

T Lymphocytes ◽

Prospective Study ◽

A Prospective Study ◽

Lymphocytes Subsets

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Detection of JC Virus-Specific Cytotoxic T Lymphocytes in Healthy Individuals

Journal of Virology ◽

10.1128/jvi.78.18.10206-10210.2004 ◽

2004 ◽

Vol 78 (18) ◽

pp. 10206-10210 ◽

Cited By ~ 64

Author(s):

R. A. Du Pasquier ◽

J. E. Schmitz ◽

J. Jean-Jacques ◽

Y. Zheng ◽

J. Gordon ◽

...

Keyword(s):

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Mononuclear Cells ◽

Demyelinating Disease ◽

Jc Virus ◽

T Cell Response ◽

Healthy Individuals ◽

Peripheral Blood Mononuclear ◽

Specific Ctls ◽

The Central Nervous System

ABSTRACT The polyomavirus JC (JCV) infects 85% of healthy individuals, and its reactivation in a limited number of immunosuppressed people causes progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system. We hypothesized that JCV-specific cytotoxic T lymphocytes (CTLs) might control JCV replication in healthy individuals, blocking the evolution of PML. Using 51Cr release and tetramer staining assays, we show that 8 of 11 HLA-A*0201+ healthy subjects (73%) harbor detectable JCV-specific CD8+ CTLs that recognize one or two epitopes of JCV VP1 protein, the HLA-A*0201-restricted VP1p36 and VP1p100 epitopes. We determined that the frequency of JCV VP1 epitope-specific CTLs varied from less than 1/100,000 to 1/2,494 peripheral blood mononuclear cells. More individuals had JCV VP1-specific than cytomegalovirus-specific CTLs (8 of 11 subjects [73%] versus 2 of 10 subjects [20%], respectively). These results show that a CD8+-T-cell response against JCV is commonly found in immunocompetent people and suggest that these cells might protect against the development of PML.

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Frequency and Phenotype of JC Virus-Specific CD8+ T Lymphocytes in the Peripheral Blood of Patients with Progressive Multifocal Leukoencephalopathy

Journal of Virology ◽

10.1128/jvi.01809-06 ◽

2007 ◽

Vol 81 (7) ◽

pp. 3361-3368 ◽

Cited By ~ 37

Author(s):

Marco A. Lima ◽

Angela Marzocchetti ◽

Patrick Autissier ◽

Troy Tompkins ◽

Yiping Chen ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Progressive Multifocal Leukoencephalopathy ◽

Jc Virus ◽

Study Groups ◽

Bk Virus ◽

Effector Memory ◽

Color Flow ◽

Significant Difference ◽

Effector Memory Cells

ABSTRACT JC virus (JCV)-specific CD8+ cytotoxic T lymphocytes (CTL) are associated with a favorable outcome in patients with progressive multifocal leukoencephalopathy (PML) and cross-recognize the polyomavirus BK virus (BKV). We sought to determine the frequency and phenotype in fresh blood of CD8+ T cells specific for two A*0201-restricted JCV epitopes, VP1p36 and VP1p100, and assess their impact on JC and BK viremia and viruria in 15 healthy subjects, eight human immunodeficiency virus-positive (HIV+) individuals, and nine HIV+ patients with PML (HIV+ PML patients) classified as survivors. After magnetic preenrichment of CD8+ T cells, epitope-specific cells ranged from 0.001% to 0.22% by tetramer staining, with no significant difference among the three study groups. By use of seven-color flow cytometry, there was no predominant differentiation phenotype subset among JCV-specific CD8+ T cells in healthy individuals, HIV+ subjects, or HIV+ PML patients. However, in one HIV+ PML patient studied in the acute phase, there was a majority of activated effector memory cells. BKV DNA was undetectable in all blood samples by quantitative PCR, while a low JC viral load was found in the blood of only one HIV+ and two HIV+ PML patients. JCV and BKV DNA were detected in 33.3% and 13.3% of all urine samples, respectively, independent of the presence of JCV-specific CTL. The detection of JCV DNA in the urine was associated with the presence of a JCV VP1p100 CTL response. Immunotherapies aiming at increasing the cellular immune response against JCV may be valuable in the treatment of HIV+ individuals with PML.

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