Impact of endogenous retroviruses in the domestic dog

ABSTRACT The replication cycle of retrovriuses is unique among mammalian viruses in the obligatory step of integrating a chromosomal copy of the infecting viral genome as a provirus. Consequently, infection of germline DNA may lead to a provirus that is transmitted to the host’s offspring. The integrant is thereafter referred to as an

endogenous retrovirus (ERV) and may, over time, reach species fixation. ERVs have contributed to abundant proportions of many species’ genomes (e.g., over 8 and 10% of the human and mouse genomes, respectively) and are recognized as mediators of genomic variation and disease. ERV-encoded gene functions have been

multiply co-opted for roles of syncytial formation, receptor blocking and other modes of protection, as well as immune modulation; their regulatory structures have been coopted for functions in gene activation, enhancers, and splice sites. Expressed ERV products are also present in cancers. In humans, ERVs are deregulated in

cancers in the form of RNAs, enzyme activities, and even particles in tumor-matched studies. While the consequences of this expression being disentangled, it is clear from animal models of human disease that replicative activity and proteins derived from related ERVs cause aberrant cellular proliferation, drive

tumorigenesis, and to incite immune responses. Thus, animal models are essential to our understanding of ERV-host outcomes and to establish links between closely related HERV groups and disease. The genomes of several species, including human, are known to harbor ERV lineages with recent or ongoing infectious activity.

These lineages tend to include copies with insertional polymorphism (i.e., unfixed), conserved sequence, as well as open reading frames (ORFs). In the domestic dog, retroviral particles and enzyme activity have been reported in lymphomas and canine cell lines support retrovirus replication from several host species including

human. Early claims of dog XRVs were not substantiated, and consequently retrovirus interplay in this species have been ignored. Thus, there is a significant gap in our understanding of virus-host relationships in this species. We have shown retroviruses have indeed recently infected canines as evident from high levels of an

unfixed g-like ERV in dog genomes, ERV-Fc1, a chimeric ERV related to the human gERV-W(syncytin-like; env) and gERV-Fc (LTRs, gag, pro/pol) associated with human cancers. Mobilization of existing ERVs by complementation had a significant role in Fc1 expansion in the dog. We show that Fc1 are expressed and

significantly upregulated in canine tumors, including ones that possess ORFs. The objective of this proposal is to span an existing knowledge gap by characterizing virus-host coevolution and impact in a uniquely opportune context of the dog by: 1) characterizing the functional properties of naturally occurring and reconstructed

genes; 2) defining Fc1 promoter activities; 3) examining the outcomes of ERV deregulation in health and disease. This work has significance to advance basic and clinical research fronts in ERV activities, functions, and pathogenicity in the dog model and a variant resource for human comparative analyses.