1401. Cellular Immune Exhaustion in Progressive Multifocal Leukoencephalopathy (PML)
Session: Oral Abstract Session: Host Susceptibility to Viral Infections
Sunday, October 23, 2011: 8:30 AM
Room: 156ABC
Background: 

Progressive multifocal leukoencephalopathy (PML) is a deadly brain disease caused by the polyomavirus JC (JCV).  While up to 80% of adults are seropositive, JCV reactivation resulting in PML occurs in immunosuppressed individuals, including patients with HIV, transplantation, and individuals treated with monoclonal antibodies.  One year survival of PML is only 50%. The presence of JCV-specific CD8+ cytotoxic T-lymphocytes (CTL) has been associated with improved survival.  Host CTL dysfunction may be due to T-cell exhaustion involving the inhibitory receptor programmed cell death 1 (PD-1). While exhausted CD8+ T-cells express high levels of PD-1 in chronic viral infections, the blockade of this pathway resulted in increased expansion of activated viral specific T-cells.  We examined the contribution of PD-1 to cellular immune dysfunction in PML.

Methods: 

We enrolled 30 subjects, including10 HIV+ and 10 HIV- PML patients, 5 HIV+ and 5 healthy control subjects.  We measured PD-1 expression on CD4+ and CD8+ T-cells, as well as on JCV-specific CD8+ T cells by flow cytometry.  Furthermore, we tested effects of PD-1 blockade on JCV-specific CTL function by measuring interferon-gamma (IFN-γ) production of JCV peptide-stimulated CTL.

Results: 

The mean PD-1 expression level on CD8+ T-cells was 29% in PML patients compared to 14% in healthy individuals (p=0.027), and 41% in HIV+ controls.  The mean PD-1 expression level on CD4+ T-cells was 36% in PML patients compared to 13% in healthy individuals (p=0.005), and 35% in HIV+ controls.  There was no significant difference between PD-1 expression levels on T-cells from HIV+ and HIV- PML patients.  However, in PML patients, the PD-1 expression level of JCV-specific CD8+ T-cells was significantly higher than that of total CD8+ T-cells.  No such difference was detected in the HIV+ and the healthy control groups.  Blockade of PD-1 receptor increased IFN-g expression in JCV-specific CTL after specific peptide stimulation.

Conclusion: 

Increased PD-1 expression on JCV-specific CTL suggests that immune exhaustion may play a role in the pathogenesis of PML.  Augmentation of JCV cellular immune response through PD-1 blockade deserves further evaluation as a form of immunotherapy for this incurable disease.


Subject Category: V. Virology including clinical and basic studies of viral infections, including hepatitis

C. Sabrina Tan, MD1, Evelyn Bord2, Thomas Broge Jr.2, Brett Glotzbecker, MD2, Heidi Mills2, Sarah Gheuens, MD3, Jacalyn Rosenblatt, MD4, David Avigan, MD2 and Igor Koralnik, MD5, (1)Medicine, Beth Israel Deaconess Medical Center/ Harvard Medical School, Boston, MA, (2)Beth Israel Deaconess Medical Center, Boston, MA, (3)Neurology, Beth Israel Deaconess Medical Center/ Harvard Medical School, Boston, MA, (4)Medicine, Beth Israel Deaconess Medical Center, Boston, MA, (5)Neurology, Beth Israel Deaconess Medical Center / Harvard Medical School, Boston, MA

Disclosures:

C. S. Tan, None

E. Bord, None

T. Broge Jr., None

B. Glotzbecker, None

H. Mills, None

S. Gheuens, None

J. Rosenblatt, None

D. Avigan, None

I. Koralnik, None

Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.