Comparative Pathogenesis of Epsilonretroviruses

Abstract

Experimental models using mammalian and avian oncogenic retroviruses have led to key advances in the understanding of cell proliferation and oncogenesis and basic principles in cell biology. Since the discovery in 1911 of Rous sarcoma virus (65,66), more than 30 oncogenes have been identified in acutely transforming simple retroviruses (reviewed in references 17 and 62). Retrovirally transduced oncogenes include transcription factors, growth-stimulating factors, receptor molecules, protein tyrosine kinases, protein serine/threonine kinases, and membrane-associated G proteins (62). Each of these retrovirus-encoded oncogenes has a highly conserved cellular counterpart, and many of their human homologs have been implicated in cancers. In contrast to the simple retroviruses, oncogenic complex retroviruses, e.g., human T-cell lymphotropic virus type 1, do not contain typical oncogenes but contain unique regulatory and accessory genes that are believed to promote cancer through their ability to alter cellular gene regulation (1). These studies have contributed greatly to our understanding of eucaryotic cell cycle regulation and cell proliferation, but these processes are still far from understood. Therefore, it is important to continue to develop new research venues for the study of cell proliferation, including new systems to study retrovirus-induced oncogenesis. Piscine and other retroviruses of lower vertebrates represent an untapped resource of model systems to investigate mechanisms of oncogenesis. At least 13 proliferative lesions of fish are tentatively attributed to retroviruses based on the observation of retrovirus-like particles and, in some cases, reverse transcriptase activity in lesions. Interestingly, seven of these lesions are seasonal; i.e., they develop and regress annually, thereby providing unique experimental models for tumor development and naturally occurring tumor death (Table 1) (25). This review focuses on the skin lesions of walleyes (Stizostedion vitreum), i.e., walleye dermal sarcoma (WDS) and walleye epidermal hyperplasia (WEH) and on their associated epsilonretroviruses, WDS virus (WDSV) and WEH viruses 1 and 2 (WEHV1 and WEHV2). WDS AND EPIDERMAL HYPERPLASIAWDS and WEH were first reported on fish from Oneida Lake in New York by Walker (76), who later observed type C retrovirus-like particles in lesions (75, 76). Subsequently, WDS and WEH have been reported on walleyes throughout North America (9, 79). Both WDS and WEH are common in areas of endemicity; nearly 30% of the adult walleyes collected during the spring spawning run from Oneida Lake present WDS in some years, while approximately 10% present WEH. Lesions are present in late fall through early spring, when they regress ( Fig. 1) (2,11,25,60). WDS of feral walleyes is a multifocal, benign skin lesion that can first be seen in the fall as firm, vascularized tumors (Fig. 1). In contrast, WEH is a multifocal hyperproliferative skin disease that can first be seen in the fall as sharply delimited plaques of thickened epidermis (Fig. 1)...

Identification and Characterization of an Exogenous Retrovirus from Atlantic Salmon Swim Bladder Sarcomas

“…The structural and transcriptional profile of SSSV indicates that it is a simple retrovirus; there is, at most, only one potential coding region in the leader in addition to gag, pol, and env. Consequently, SSSV appears different from exogenous piscine retroviruses of the Epsilonretrovirus genus which express two ORFs downstream of env (18). Although structurally similar to simple retroviruses, SSSV is distinguished from them in that no related endogenous counterparts have been identified in the Atlantic salmon genome.…”

“…Molecular characterization of these viruses from their associated skin proliferative diseases has provided insights into their mechanisms of pathogenesis. In particular, all three viruses share a complex structure and express distant cyclin homologs presumably involved in tumorigenesis (18,19,25,34). Interestingly, WDSVand WEHV-associated neoplasms have been documented to appear and regress seasonally, suggesting a complex regulation of tumor progression in these systems (11).…”

Comparative study of tumorigenesis and tumor immunity in invertebrates and nonmammalian vertebrates

“…Skin neoplasms in bony fish include tumors in pigmented skin cells such as melanoma but also erythrophoromas and iridophoromas that are not found in mammals [50]. Interestingly, several retroviruses have been found associated with neoplasia in bony fish [51]. The best known is the Walleye dermal sarcoma virus (WDSV) that has been etiologically linked to the development of Walleye dermal sarcoma, a common skin neoplastic disease of walleye fish ( Sander vitreus ) in the United States and Canada [52].…”

Relevant Oncogenic Viruses in Veterinary Medicine: Original Pathogens and Animal Models for Human Disease

“…ORFs A and B appear to be gene duplicates immediately downstream of the 3Ј-LTR and encode a cyclin homolog, rv-cyclin [24]. This protein interacts with cellular cyclin-dependent kinases (CDKs) and may cause cell proliferation by enhanced expression of some cellular genes [25]. WDSV cyclin has been shown to interact with CDK8, and therefore the mechanism of transformation may be similar to that of Kaposi sarcoma herpesvirus (KSHV/HHV-8) in Kaposi sarcoma [26].…”