Abstract
Human polyomavirus BK (BKV) has been implicated in oncogenic transformation. Its ability to replicate is determined by the binding of its large tumor antigen (LTag) to products of tumor-suppressor genes regulating cell cycle, as specifically p53. We investigated CD8+ T immune responses to BKV LTag portions involved in p53 binding in HLA-A*0201+ BKV LTag experienced individuals.Peptides selected from either p53-binding region (LTag351–450 and LTag533–626) by current algorithms and capacity to bind HLA-A*0201 molecule were used to stimulate CD8+ T responses, as assessed by IFN-γ gene expression ex vivo and detected by cytotoxicity assays following in vitro culture.We observed epitope-specific immune responses in all HLA-A*0201+ BKV LTag experienced individuals tested. At least one epitope, LTag579–587; LLLIWFRPV, was naturally processed in non professional antigen presenting cells and induced cytotoxic responses with CTL precursor frequencies in the order of 1/20'000. Antigen specific CD8+ T cells were only detectable in the CD45RA+ subset, in both CCR7+ and CCR7- subpopulations.These data indicate that widespread cellular immune responses against epitopes within BKV LTag-p53 binding regions exist and question their roles in immunosurveillance against tumors possibly associated with BKV infection.
Highlights
Human polyomavirus BK (BKV) is a DNA virus belonging to the Polyomaviridae family that includes human polyomavirus JC (JCV), and Simian virus 40 (SV40) (International Committee on the Taxonomy of Viruses (ICVD))[1]
Polyomavirus large tumor-antigen (LTag) interacts with a number of host molecules involved with cell cycle, including the tumor-suppressor gene product p53 and has been identified as an important target of cancer immunity in murine models[38]
Studies in SV40 infected mice have reported on conserved CD8+ T cells immune responses against SV40 large tumor antigen (LTag)[39]
Summary
Human polyomavirus BK (BKV) is a DNA virus belonging to the Polyomaviridae family that includes human polyomavirus JC (JCV), and Simian virus 40 (SV40) (International Committee on the Taxonomy of Viruses (ICVD))[1]. Serological evidence indicates that nearly 90% of individuals are infected by early childhood, a decrease in this rate during the human lifespan may be due to viral seroconversion (70–80%) [4,5]. When the immune system is compromised, as following transplantation, HIV infection, chemotherapy or pharmacologic immunosuppression, rate and level of BKV replication increase and may lead to organ diseases[6]. The polyomavirusencoded early gene product large tumor antigen (LTag) has been identified early on as a key regulatory molecule[7]. LTag interacts with a number of host cell molecules including the tumor-suppressor gene retinoblastoma family (Rb) products and p53. The LTag binds to products of the Rb-family (pRb, p107, and p130) thereby interfering with their activity and inducing the infected cell to enter the cell cycle (phase S). And most importantly, the LTag inactivation of p53 allows the re-phosphorylation of pRb through the cyclin-dependent kinase (cdk) pathway and prevents the p53-mediated cell apoptosis of infected cell[8]
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