Restoration of Endogenous Retrovirus Infectivity Impacts Mouse Cancer Models

Abstract

Mouse models have been instrumental in establishing fundamental principles of cancer initiation and progression and continue to be invaluable in the discovery and further development of cancer therapies. Nevertheless, important aspects of human disease are imperfectly approximated in mouse models, notably the involvement of endogenous retroviruses (ERVs). Replication-defective ERVs, present in both humans and mice, may affect tumor development and antitumor immunity through mechanisms not involving infection. Here, we revealed an adverse effect of murine ERVs with restored infectivity on the behavior of mouse cancer models. In contrast to human cancer, where infectious ERVs have never been detected, we found that ERV infectivity was frequently restored in transplantable, as well as genetic, mouse cancer models. Such replication-competent, ERV-derived retroviruses were responsible for unusually high expression of retroviral nucleic acids and proteins in mouse cancers.Infectious ERV-derived retroviruses produced by mouse cancer cells could directly infect tumor-infiltrating host immune cells and fundamentally modified the host's immune defenses to cancer, as well as the outcome of immunotherapy. Therefore, infectious retroviruses, variably arising in mouse cancer models, but not in human cancer, have the potential to confound many immunological studies and should be considered as a variable, if not altogether avoided.

Immunotherapy-induced antibodies to endogenous retroviral envelope glycoprotein confer tumor protection in mice

“…Just as eMLV is expressed by different mouse cell lines, human ERV-K (HERV-K) is expressed by numerous human tumors [ 48 ]. However, a key distinction between human and murine ERVs is that eMLV can reconstitute infectious virions [ 49 ] that can negatively impact the murine immune system [ 49 , 50 ], suggesting that successful immunotherapies must mount both antitumor and antiviral immune responses. By contrast, there has been no report of replication-competent HERV in humans [ 51 ], suggesting that cell-surface env of HERV-K may be a bona fide therapeutic target.…”

Host–transposon interactions: conflict, cooperation, and cooption

“…Recently, a pair of KRAB-ZFPs, known as Suppressor of nonecotropic ERV1 (Snerv1) and Snerv2 were shown via genetic analysis to be required for silencing of nonecotropic ERV (NEERV) expression (Treger et al 2019). In immunodeficient mice, NEERV loci can recombine to generate infectious retroviruses, and expression of NEERV glycoprotein gp70 contributes to lupus nephritis susceptibility Ottina et al 2018). Similar to ZFP809, SNERV1 recruits KAP1 to silence NEERV elements by binding sequences overlapping their LTR, in-cluding a glutamine tRNA primer-binding site (Treger et al 2019).…”

The Lupus Susceptibility Locus Sgp3 Encodes the Suppressor of Endogenous Retrovirus Expression SNERV

“…As with exogenous retroviruses, infectious ERVs, originally identified in constitutively viremic mouse strains, are appreciated for their role in malignant transformation (Kassiotis, 2014;Kozak, 2014). Additionally, in certain immune-deficient murine backgrounds and cancer-cell lines, ERV transcripts from mousetropic (i.e., ecotropic) and non-ecotropic ERV (NEERV) loci recombine to generate infectious ERVs (Ottina et al, 2018;Young et al, 2012;Yu et al, 2012). Thus, transcriptional silencing of genomic ERV sequences is a critical layer of defense from active retrotransposition, restoration of infectivity, and insertional mutagenesis leading to oncogenesis.…”