Credit: The Stock Solution

Endogenous retroviruses (ERVs) are non-functional remnants of ancient viral infections and constitute a substantial proportion of the mammalian genome. Some mouse strains are prone to ERV-induced pathologies, including tumour formation, whereas other mouse strains, such as the C57BL/6 strain, are resistant. Two studies published in Immunity and Nature now describe mechanisms involving Toll-like receptor 3 (TLR3), TLR7, TLR9 and antibodies that control ERV infectivity.

mechanisms involving Toll-like receptor 3 (TLR3), TLR7, TLR9 and antibodies that control ERV infectivity

The sensing of exogenous retroviruses in the cytoplasm by nucleic acid-sensing TLRs has an important role in controlling these viruses, so Yu et al. sought to determine whether these TLRs also have a role in the response to ERVs. Indeed, the emergence of infectious ERVs was observed in aged triple-deficient Tlr3−/−Tlr7−/−Tlr9−/− C57BL/6 mice. TLR7 was shown to have a central role in the control of ERV viraemia, with indirect roles for TLR3 and TLR9. Furthermore, the loss of TLR3, TLR7 and TLR9 resulted in the premature death of aged mice owing to the development of pre-T cell acute lymphoblastic leukaemia (T-ALL). By generating a T-ALL tumour cell line (termed Baki-1 cells) from Tlr3−/−Tlr7−/−Tlr9−/− mice, the authors showed that retroviral integration into genomic DNA led to dysregulation of T cell-specific oncogenes, giving rise to T cell transformation.

But how does TLR signalling inhibit ERVs in wild-type mice? Exogenous infection of C57BL/6 mice with ERVs isolated from Baki-1 cells resulted in the expression of genes encoding acute-phase proteins in a TLR-dependent manner. Furthermore, ERV-resistant mouse strains expressed high levels of ERV-specific neutralizing antibodies, whereas these antibodies were absent in susceptible mouse strains, including in Tlr3−/−Tlr7−/−Tlr9−/− mice. The production of these antibodies was shown to be TLR7 dependent.

Young et al. also describe a role for antibodies in the control of infectious ERVs. In this study, the authors first determined the role of the adaptive immune system in preventing the establishment of infectious viruses derived from ERVs. They found that Rag1−/− mice (which lack functional B and T cells), but not wild-type C57BL/6 mice, harboured infectious ecotropic murine leukaemia viruses (eMLVs) that were transmitted vertically to progeny.

Next, the authors showed that the presence of infectious eMLVs in these mice was due to a defect in antibody production. Of note, the expression of eMLV genes was markedly increased in Tlr7−/− mice. Similar to the observations in the study by Yu et al., aged Rag1−/− mice had increased morbidity compared with wild-type mice owing to the development of retrovirus-induced lymphomas.

Both studies associated distinct innate and adaptive immune deficiencies with the establishment of pathogenic infectious MLVs. However, in contrast to the study by Yu et al., the study by Young et al. suggested that innate and adaptive immune components were controlling exposure to unrelated environmental microorganisms. The authors suggested that immune deficiency increased the translocation of microbial products from intestinal bacteria into the systemic circulation, which in turn activated ERVs. This was supported by the observation that neither Rag1−/− nor Tlr7−/− mice lost control of their ERVs if they were housed under conditions in which microbial exposure was reduced or prevented.

Together, these studies highlight the importance of the innate and adaptive immune system for the control of ERVs in mice with selective immune deficiencies.