Human endogenous retrovirus-derived peptide epitopes presented by HLA molecules on tumor cells and antigen-presenting cells (HERV-derived epitopes)

Human endogenous retrovirus (HERV)-derived peptide epitopes are a class of tumor-associated antigens originating from the reactivation of ancient viral sequences integrated into the human genome (Bonaventura et al., 2022). While typically silenced by epigenetic mechanisms in healthy adult tissues, these sequences—comprising approximately 8% of the human genome—become transcriptionally active in various malignancies, including renal cell carcinoma, breast cancer, and melanoma (Saini et al., 2020). Once expressed, HERV proteins are processed by the proteasome and presented as short peptide fragments on the cell surface by Human Leukocyte Antigen (HLA) class I molecules (Kobayashi et al., 2023). These peptide-HLA complexes serve as potent targets for the adaptive immune system, specifically CD8+ cytotoxic T cells, which can recognize them as non-self or altered-self due to their viral origin (Bonaventura et al., 2022). Therapeutic strategies targeting these epitopes include the development of cancer vaccines and TCR-engineered T-cell therapies designed to induce or provide a robust anti-tumor immune response (Cancer.gov, 2025). Additionally, hypomethylating agents like azacitidine and decitabine are utilized to intentionally derepress HERV expression, a phenomenon known as viral mimicry, which enhances the visibility of tumor cells to the immune system and synergizes with checkpoint inhibitors (Saini et al., 2020). Because these epitopes are often shared across patients with the same HLA type, they represent a promising reservoir of off-the-shelf targets for immunotherapy, particularly in tumors with low mutational burden where traditional neoantigens are scarce (Bonaventura et al., 2022).

Other names

Human endogenous retrovirus-derived antigensHERV-derived tumor-associated antigensHERV-derived neoantigensEndogenous retroviral epitopesHERV-derived pMHC complexesHERV-derived T-cell epitopes

T-cell mediated cytotoxicity, induction of viral mimicry through DNA demethylation, and enhancement of antigen presentation.