First Look at Key Viral Protein Could Improve Diagnosis of Autoimmune Diseases

Around 8% of the human genome comes from ancient viruses embedded during evolution, a part of the genome referred to as "dark matter." These viral remnants, called human endogenous retroviruses (HERVs), usually remain silent but can reawaken in disease states. They appear in certain cancers, autoimmune disorders, and neurodegenerative diseases. Scientists have now solved the first-ever 3D structure of a human HERV protein, offering a new pathway for diagnostics and therapies.

Researchers at the La Jolla Institute for Immunology (La Jolla, CA, USA) mapped the envelope glycoprotein (Env) of HERV-K, the most active retrovirus of its kind. Env proteins were historically impossible to study because of their instability, often unfolding before analysis. To preserve its natural shape, the team introduced stabilizing substitutions and used cryo-electron microscopy to capture the protein in its pre-fusion, infection-driving, and antibody-bound states.

The study, published in Science Advances, revealed that unlike HIV or SIV trimers, HERV-K Env has a tall, lean trimeric structure with a unique fold. This breakthrough marks a milestone in structural biology, as it is the first human HERV protein structure ever solved and only the third retroviral envelope structure solved overall. The team also developed antibodies to anchor the protein and visualize its various subunits, providing the first clear understanding of how immune responses target these molecules.

Importantly, HERV-K Env proteins appear on the surface of cancer cells—including breast and ovarian tumors—but not on healthy cells. This makes them an attractive target for cancer immunotherapies that can distinguish diseased from healthy tissue. Similarly, autoimmune patients like those with lupus or rheumatoid arthritis show aberrant HERV expression, suggesting the protein could serve as a diagnostic biomarker for immune-driven disease.

The discovery also provides insight into why immune cells sometimes mistakenly attack the body. The team demonstrated that their engineered antibodies could detect abnormal HERV expression on neutrophils in patient samples but not in healthy individuals. These findings highlight HERV-K Env’s potential as both a research tool and a clinical marker across oncology, immunology, and neurology.

“In many disease states, like autoimmune diseases and cancer, these genes re-awaken and start making pieces of these viruses,” said Erica Ollmann Saphire, Ph.D., MBA, President and CEO of the La Jolla Institute for Immunology. “Understanding the HERV-K Env structure, and the antibodies we now have, opens up diagnostic and treatment opportunities.”

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La Jolla Institute for Immunology