Recycled endogenous retroviruses drive innate antiviral cascades against exogenous retroviral infection

Endogenous retroviruses (HERVs), the relics of ancient viral integrations are increasingly emerging as active wiring within our genome, functioning as cis-regulatory elements that control nearby immune genes. This seminar will highlight evidence, including from our own lab, that HERVs assemble stress-responsive gene-regulatory networks operating both locally (in cis) and at a distance (in trans) to fine-tune immune activation and inflammatory balance across diverse biological contexts, from placenta to brain to blood. A striking human example comes from HIV elite controllers; a rare group of individuals who suppress HIV without therapy whose CD4 T cells are marked by a distinctive repertoire of transcriptionally active HERVs regulating nearby antiviral factors. Beyond cis regulation, the human genome also retains a reservoir of HERV sequences capable of encoding viral gag and envelope proteins with the power to reshape cellular physiology: some envelopes can protect cells by blocking viral entry, exemplifying viral genes repurposed for host defence, while our data suggest that gag and certain envelopes, reactivated in cancers or during immune activation can perturb distant tissues, including the CNS, forging unexpected connections between cancer progression and neurodegeneration. Together, these findings reveal an underappreciated continuum across immunity, cancer and brain health, where “recycled” retroelements can be protective in one context yet pathogenic when mis-expressed in another.