We identified a GPC3367-specific T-cell receptor. Expression of this receptor by T cells allows them to recognize and kill GPC3-positive hepatoma cells. This finding could be used to advance development of adoptive T-cell therapy for HCC.

The polyomavirus tumor (T) antigens play crucial roles in viral replication IMPORTANCEThe human trichodysplasia spinulosa-associated polyomavirus (TSPyV) is distinguished among polyomaviruses for combining productive infection with cell-transforming properties. In the research presented here, we further substantiate this unique position by indicating expression of both middle T antigen (MT) and alternative T antigen (ALTO) in TSPyV. So far, none of the human polyomaviruses was shown to express MT, which is considered the most important viral oncoprotein of rodent polyomaviruses. Coexpression of ALTO and MT, which involves a conserved, recently recognized overlapping ORF subject to positive selection, has not been observed before for any polyomavirus. As a result of our findings, this study provides valuable new insights into polyomavirus T gene use and expression. Obviously, these insights will be instrumental in further study and gaining an understanding of TSPyV pathogenicity. More importantly, however, they provide important leads with regard to the interrelationship, functionality, and evolution of polyomaviruses as a whole, indicating that TSPyV is a suitable model virus to study these entities further.H uman polyomaviruses represent a rapidly expanding group of small, circular double-stranded DNA viruses that persistently infect the general population, usually without causing symptoms (1-6). Seven of 13 described human polyomaviruses have been associated with disease in immunocompromised individuals, i.e., JC polyomavirus (JCPyV) (7), BK polyomavirus (BKPyV) (8), Merkel cell polyomavirus (MCPyV) (9), trichodysplasia spinulosa-associated polyomavirus (TSPyV) (10, 11), human polyomavirus 6 (HPyV6) (12), human polyomavirus 7 (HPyV7) (13), and New Jersey polyomavirus (NJPyV) (14, 15). MCPyV and TSPyV, which belong to orthopolyomavirus lineage I (3, 16), are associated with a malignant and a benign hyperproliferative skin disease called Merkel cell carcinoma (MCC) and trichodysplasia spinulosa (TS), respectively. The hyperproliferative phenotype of both diseases indicates involvement of the viral tumor (T) antigens in the patho(onco)genesis.T antigens that play a coordinating role in viral transcription and replication are generally known for their ability to disrupt cellular pathways involved in cell cycle regulation and signaling (17,18). The large T antigen (LT), for example, promotes cell cycle entry through inactivation (hyperphosphorylation) of pRB, as demonstrated, for example, for simian virus 40 (SV40) (18,19).

T-cell therapy of chronic hepatitis B is a novel approach to restore antiviral T-cell immunity and cure the infection. We aimed at identifying T-cell receptors (TCR) with high functional avidity that have the potential to be used for adoptive T-cell therapy. To this end, we cloned HLA-A*02-restricted, hepatitis B virus (HBV)-specific T cells from patients with acute or resolved HBV infection. We isolated 11 envelope- or core-specific TCRs and evaluated them in comprehensive functional analyses. T cells were genetically modified by retroviral transduction to express HBV-specific TCRs. CD8+ as well as CD4+ T cells became effector T cells recognizing even picomolar concentrations of cognate peptide. TCR-transduced T cells were polyfunctional, secreting the cytokines interferon gamma, tumor necrosis factor alpha and interleukin-2, and effectively killed hepatoma cells replicating HBV. Notably, our collection of HBV-specific TCRs recognized peptides derived from HBV genotypes A, B, C and D presented on different HLA-A*02 subtypes common in areas with high HBV prevalence. When co-cultured with HBV-infected cells, TCR-transduced T cells rapidly reduced viral markers within two days. Our unique set of HBV-specific TCRs with different affinities represents an interesting tool for elucidating mechanisms of TCR-MHC interaction and dissecting specific anti-HBV mechanisms exerted by T cells. TCRs with high functional avidity might be suited to redirect T cells for adoptive T-cell therapy of chronic hepatitis B and HBV-induced hepatocellular carcinoma.

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