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Interplay of Cellular and Humoral Immune Responses against BK Virus in Kidney Transplant Recipients with Polyomavirus Nephropathy

Yiping Chen,¹ Jennifer Trofe,^2, Jennifer Gordon,³ Renaud A. Du Pasquier,^1,4, Prabir Roy-Chaudhury,² Marcelo J. Kuroda,^1, E. Steve Woodle,² Kamel Khalili,³ and Igor J. Koralnik^1,4*

Division of Viral Pathogenesis,¹ Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts,⁴ Division of Transplantation, University of Cincinnati, Cincinnati, Ohio,² Center for Neurovirology and Department of Neuroscience, Temple University School of Medicine, Philadelphia, Pennsylvania³

Received 7 November 2005/ Accepted 13 January 2006

Reactivation of the polyomavirus BK (BKV) causes polyomavirus nephropathy (PVN) in kidney transplant (KTx) recipients and may lead to loss of the renal allograft. We have identified two HLA-A*0201-restricted nine-amino-acid cytotoxic T lymphocyte (CTL) epitopes of the BKV major capsid protein VP1, VP1_p44, and VP1_p108. Using tetramer staining assays, we showed that these epitopes were recognized by CTLs in 8 of 10 (VP1_p44) and 5 of 10 (VP1_p108) HLA-A*0201⁺ healthy individuals, while both epitopes elicited a CTL response in 10 of 10 KTx recipients with biopsy-proven PVN, although at variable levels. After in vitro stimulation with the respective peptides, CTLs directed against VP1_p44 were more abundant than against VP1_p108 in most healthy individuals, while the converse was true in KTx recipients with PVN, suggesting a shift in epitope immunodominance in the setting of active BKV infection. A strong CTL response in KTx recipients with PVN appeared to be associated with decreased BK viral load in blood and urine and low anti-BKV antibody titers, while a low or undetectable CTL response correlated with viral persistence and high anti-BKV antibody titers. These results suggest that this cellular immune response is present in most BKV-seropositive healthy individuals and plays an important role in the containment of BKV in KTx recipients with PVN. Interestingly, the BKV CTL epitopes bear striking homology with the recently described CTL epitopes of the other human polyomavirus JC (JCV), JCV VP1_p36 and VP1_p100. A high degree of epitope cross-recognition was present between BKV and corresponding JCV-specific CTLs, which indicates that the same population of cells is functionally effective against these two closely related viruses.

Present address: Department of Pharmacy Service, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104-4322.

Present address: Divisions of Neurology and Immunology, BT02- 251, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.

Present address: Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433.

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