A weakened immune system leads to retroviral awakening

25 October 2012

NIMR scientists have described previously unknown retroviruses in mice, and a potential link between infection and cancer. The research is published online in Nature.

All mammals, including humans, have a long-standing symbiotic relationship with a considerable number of microbial species, such as microbiota in the respiratory and gastrointestinal tracts, and endogenous retroviruses (ERVs) present in the genome. Half of the genome is composed of transposable retroelements like ERVs, which are relics of ancestral retroviral infection. Most, if not all, ERVs have become inactive due to mutations or transcriptionally silenced through the action of diverse mechanisms. However, RNA and protein expression of replication-defective ERVs is frequently elevated in infection, autoimmunity and cancer. Whether or not the immune system defends against potential threats posed by ERVs is currently unclear.

George Kassiotis (pictured), from the Division of Immunoregulation, and Jonathan Stoye, from the Division of Virology, have studied the control of ERVs in a commonly-used mouse strain, C57BL/6 (B6), which lacks endogenous murine leukaemia viruses (MLVs) able to replicate in murine cells. They studied mice with specific congenital immunodeficiencies and monitored the emergence of pathogenic viruses derived from ERVs. They demonstrated the spontaneous emergence of fully infectious ecotropic MLV in B6 mice that had a range of distinct immune deficiencies affecting antibody production.

These recombinant retroviruses ultimately result in retrovirus-induced lymphomas. ERV activation in immune-deficient mice is prevented in husbandry conditions associated with reduced or absent intestinal microbiota.

These results shed light on a previously unappreciated role for immunity in the control of ERVs and provide a potential mechanistic link between immune activation by microbial triggers and a range of pathologies associated with ERVs, including cancer. Our results demonstrate that whether or not replication-defective ERVs can become pathogenic in mice is very much dependent on their immune status.

George Kassiotis

Our results show that in immunodeficient mice, increased exposure to other microbes (including intestinal commensals) drives replication-defective ERVs to repair their defects and give spontaneous rise to fully infectious pathogenic viruses that eventually cause cancer. This presumed dead enemy within is resurrected in immunodeficiency. We are currently examining whether human disease can arise in a similar manner.

Jonathan Stoye

Click image to view at full-size

Numerous retroviral particles (pseudocoloured) in the extracellular spaces of a lymphoma resected from a lymphocyte-deficient Rag1-/- mouse.
From an EM micrograph by Liz Hirst.

Original article

George R Young, Urszula Eksmond, Rosalba Salcedo, Lena Alexopoulou, Jonathan P Stoye and George Kassiotis (2012)

Resurrection of endogenous retroviruses in antibody-deficient mice

Nature Epub ahead of print. Publisher abstract.

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