Identification and spontaneous immune targeting of an endogenous retrovirus K envelope protein in the Indian rhesus macaque model of human disease

Abstract

BackgroundEndogenous retroviruses (ERVs) are remnants of ancient retroviral infections that have invaded the germ line of both humans and non-human primates. Most ERVs are functionally crippled by deletions, mutations, and hypermethylation, leading to the view that they are inert genomic fossils. However, some ERVs can produce mRNA transcripts, functional viral proteins, and even non-infectious virus particles during certain developmental and pathological processes. While there have been reports of ERV-specific immunity associated with ERV activity in humans, adaptive immune responses to ERV-encoded gene products remain poorly defined and have not been investigated in the physiologically relevant non-human primate model of human disease.FindingsHere, we identified the rhesus macaque equivalent of the biologically active human ERV-K (HML-2), simian ERV-K (SERV-K1), which retains intact open reading frames for both Gag and Env on chromosome 12 in the macaque genome. From macaque cells we isolated a spliced mRNA product encoding SERV-K1 Env, which possesses all the structural features of a canonical, functional retroviral Envelope protein. Furthermore, we identified rare, but robust T cell responses as well as frequent antibody responses targeting SERV-K1 Env in rhesus macaques.ConclusionsThese data demonstrate that SERV-K1 retains biological activity sufficient to induce cellular and humoral immune responses in rhesus macaques. As ERV-K is the youngest and most active ERV family in the human genome, the identification and characterization of the simian orthologue in rhesus macaques provides a highly relevant animal model in which to study the role of ERV-K in developmental and disease states.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0238-0) contains supplementary material, which is available to authorized users.

Endogenous retrovirus expression is associated with response to immune checkpoint pathway in clear cell renal cell carcinoma

“…However, 66 ERVs are known to be transcribed in humans (17), and their expression has been reported in multiple cancers (18). Some recently integrated (19) and well-preserved (19) ERVs, such as those in the ERVK family, are known to retain a functional gag gene (20) and an open-reading frame in pol and env genes (20), and their simian equivalents are known to induce immune response in Indian rhesus macaques (21). Thus, abnormal expression of some potentially immunogenic ERVs (πERVs) in tumors may elicit an antitumor immune response spearheaded by CD8 + T cells.…”

Emerging diagnostic challenges and characteristics of simian betaretrovirus infections in captive macaque colonies

“…Recent publications have reported additional serotypes beyond the well‐established SRV1‐5 . We (R. Grant, manuscript submitted) and others have demonstrated confounding detection of host immune responses to endogenous viruses in SRV serology . Although both SRV5 donors were antibody positive/PCR negative on the day of transfusion, they were infected as shown by not only antibody but also PCR positivity on five of ten and one of ten dates tested during the prior 2 months.…”

Genome-wide characterization of endogenous retroviruses in snub-nosed monkeys

“…These sequences, have been detected in all vertebrates genomes including humans, and they often occupy a intermediate fraction of the genome (Blikstad et al, 2008; Gifford & Tristem, 2003). For example, ERVs contribute to approximately 8% of the human genome and 10% of the mouse genome (Griffiths, 2001; Subramanian et al, 2011; Wu et al, 2016).…”