Human endogenous retrovirus K (HERV-K) envelope structures in pre- and postfusion by cryo-EM
- Jeremy Shek
- Chen Sun
- Elise M. Wilson
- Fatemeh Moadab
- Kathryn M. Hastie
- Roshan R. Rajamanickam
- Patrick J. Penalosa
- Stephanie S. Harkins
- Diptiben Parekh
- Chitra Hariharan
- Dawid S. Zyla
- Cassandra Yu
- Kelly C. L. Shaffer
- Victoria I. Lewis
- Ruben Diaz Avalos
- Tomas Mustelin
- Erica Ollmann Saphire
2025-08-27
Human endogenous retroviruses (HERVs) are remnants of ancient infections that comprise ~8% of the human genome. The HERV-K envelope glycoprotein (Env) is aberrantly expressed in cancers, autoimmune disorders, and neurodegenerative diseases, and is targeted by patients’ own antibodies. However, a lack of structural information has limited molecular and immunological studies of the roles of HERVs in disease. Here, we present cryo–electron microscopy structures of stabilized HERV-K Env in the prefusion conformation, revealing a distinct fold and architecture compared to HIV and simian immunodeficiency virus. We also generated and characterized a panel of monoclonal antibodies with subunit and conformational specificity, serving as valuable research tools. These antibodies enabled structure determination of the postfusion conformation of HERV-K Env, including its unique “tether” helix, and antibody-bound prefusion Env. Together, these results provide a structural framework that opens the door to mechanistic studies of HERV-K Env and tools for its evaluation as a potential therapeutic target.