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.
