Ancient Viral Envelope Protein Could Spark Diagnostic And Therapeutic Revolutions

A team at the La Jolla Institute for Immunology has achieved a landmark breakthrough by unveiling the first three-dimensional structure of a viral protein deeply embedded in our DNA. Using cryo-electron microscopy, researchers captured the full architecture of the HERV‐K envelope glycoprotein, a relic of ancient viral integration now implicated in cancer, autoimmune and neurodegenerative diseases. This unprecedented insight marks the earliest structural characterisation of a human endogenous retrovirus Env protein-and only the third retroviral envelope structure ever resolved globally.

The Env protein assembled into a previously unobserved trimeric form-noticeably tall and slender compared with the shorter, wider trimers of HIV and SIV-revealing a fold strikingly unlike any known retroviral envelope. The structure was stabilized in its metastable pre‐fusion conformation through subtle protein engineering and monoclonal antibody anchoring, enabling high‐resolution imagery.

Monoclonal antibodies developed by the team played dual roles: they both maintained the Env structure in its native pre‐fusion state and facilitated capture of its post‐fusion form via cryo‐EM. The pre‐fusion Env trimer displays a novel fold dominated by β‐stranded architecture, diverging from widely studied exogenous retroviral envelopes. In its post‐fusion state, the transmembrane subunit rearranges into a six‐helix bundle with a distinctive“tether” helix, underscoring structural and mechanistic divergence.

The implications for medicine are vast. HERV‐K Env proteins are found on the surface of certain tumour cells-including breast and ovarian cancers-and on immune cells from patients with autoimmune diseases like lupus and rheumatoid arthritis. Researchers demonstrated that their engineered antibodies could specifically detect Env on neutrophils from patients, but not on those from healthy individuals-suggesting potential diagnostic and therapeutic applications.

Beyond diagnostics, the structural framework enables precise exploration of immunotherapies. Env‐targeting antibody‐drug conjugates or CAR‐T cells may one day be designed to hone in on Env‐expressing cells, offering new avenues in cancer treatment. In autoimmune conditions, further study of Env‐antibody complexes could reveal whether they drive immune system misfires or offer protective measures.

This discovery holds profound significance for structural virology. Until now, only HIV and SIV envelopes had been resolved in trimeric form; HERV‐K Env represents a structurally and evolutionarily distinct branch. Its novel β‐rich, streamlined trimer architecture adds depth to our understanding of retroviral evolution and fusion mechanics.

By providing cryo‐EM images of both pre‐ and post‐fusion configurations, anchored by bespoke antibodies, researchers have established a robust platform for mapping antibody interactions, receptor binding sites, and functional domains. This in turn lays the groundwork for rational design of vaccines, diagnostics, and antibody‐based therapies tailored to HERV‐K Env.

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