Characterization of T Antigens, Including Middle T and Alternative T, Expressed by the Human Polyomavirus Associated with Trichodysplasia Spinulosa

Abstract

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).

Emerging differential roles of the pRb tumor suppressor in trichodysplasia spinulosa-associated polyomavirus and Merkel cell polyomavirus pathogeneses

“…Thus, it is reasonable to speculate that TSPyV sT and MT share certain mechanistic properties such as the ability to regulate PP2A and its downstream targets including pRb. Given that TSPyV and MCPyV are genomically very similar and commonly express several proteins aside from the sT antigen [15,16], it is possible that MCPyV may also encode the MT antigen, although this has yet to be determined experimentally.…”

“…In particular, molecular analysis of TS lesions has revealed the presence of mRNA from TSPyV middle T (MT) antigen, which is identical to sT antigen in the first 196 amino acids and contains matching protein binding domains [15]. Thus, it is reasonable to speculate that TSPyV sT and MT share certain mechanistic properties such as the ability to regulate PP2A and its downstream targets including pRb.…”

“…While the sT antigen remains the only protein encoded by TSPyV to be mechanistically associated with cell proliferation pathways, recent studies have demonstrated that several other T antigens may also be transcribed from the overlapping open reading frames of the TSPyV genome [15]. In particular, molecular analysis of TS lesions has revealed the presence of mRNA from TSPyV middle T (MT) antigen, which is identical to sT antigen in the first 196 amino acids and contains matching protein binding domains [15].…”

Imperfect Symmetry of Sp1 and Core Promoter Sequences Regulates Early and Late Virus Gene Expression of the Bidirectional BK Polyomavirus Noncoding Control Region

“…HPyV seroprevalence data obtained using the major capsid protein Vp1 as pentamers or virus-like particles indicate that HPyVs infect 50% to 90% of the general human population without known specific signs or symptoms of disease (2)(3)(4)(5)(6)(7). As information about the virology and pathology of the 13 human PyVs is only emerging (8,9), we focused on BK polyomavirus (BKPyV) as a model (10). After primary infection in early childhood, BKPyV persists latently in the renourinary tract with periods of low-level shedding into urine (4,11,12).…”

In Vitro and In Vivo Models for the Study of Human Polyomavirus Infection

“…Genetic differences exist between mouse and human PyV, for example the mouse PyV genome encodes a third TAg named MTAg, which is the principal oncogene of mouse PyV [117]. At present, none of the human PyV has been shown to express MTAg, except TSPyV, as demonstrated recently by van der Meijden and colleagues [118]. Furthermore, unlike JCPyV and BKPyV, mouse PyV lack the agnoprotein.…”