Human Endogenous Retrovirus antigens (HERV antigens)

Human Endogenous Retrovirus (HERV) antigens are proteins encoded by ancient retroviral sequences that have been integrated into the human germline over millions of years, now constituting approximately 8% of the human genome [13, 19]. While most HERVs are epigenetically silenced in healthy adult tissues, their reactivation is strongly associated with various pathological conditions, including several types of cancer, autoimmune disorders, and neurodegenerative diseases [14, 20]. In malignancies such as breast cancer, melanoma, and renal cell carcinoma, HERV proteins like HERV-K and HERV-E act as tumor-specific neoantigens that can be targeted by immunotherapies [7, 12, 21]. In neurological conditions like multiple sclerosis, the HERV-W envelope protein (Syncytin-1) has been identified as a driver of neuroinflammation and demyelination, making it a key therapeutic target [2, 5]. Therapeutic strategies targeting HERV antigens include monoclonal antibodies, such as temelimab, which neutralizes pathogenic envelope proteins to slow disease progression in multiple sclerosis and type 1 diabetes [2, 3]. Additionally, advanced cellular therapies like CAR-T and TCR-T cells are being developed to exploit the highly specific expression of HERV antigens on tumor cells for precision oncology [10, 16]. Because these antigens are often absent or highly restricted in normal tissues, they represent a promising class of targets for reducing off-target toxicity in immunotherapy. Ongoing research continues to explore the use of HERV expression as a diagnostic and prognostic biomarker across a wide range of complex diseases [12, 18].

Other names

Endogenous retroviral proteinsHERV-K antigensHERV-W antigensHERV-E antigensSyncytin-1MSRV-EnvHML-2 antigensHERV-derived neoantigens

Drugs targeting HERV antigens primarily work through neutralization of pathogenic proteins or targeted destruction of cells expressing these antigens. For instance, the monoclonal antibody temelimab neutralizes the HERV-W envelope protein (Env) to prevent microglial activation and promote remyelination in multiple sclerosis [1, 5]. In oncology, CAR-T and TCR-T cell therapies are engineered to recognize HERV-K or HERV-E antigens on the surface of tumor cells, leading to direct cytotoxic killing of the malignant cells [7, 16]. Other approaches include using monoclonal antibodies to induce apoptosis in cancer cells or vaccines to stimulate a systemic immune response against HERV-expressing tumors [9, 10].