We are all part virus. Hidden within your DNA lies a fossil record of ancient infections that have shaped human evolution and now hold keys to understanding disease.
The human genome is often described as the blueprint of life, but it is also a museum of natural history. Nearly half of our DNA is made up of repetitive, virus-like sequences. Among these, endogenous retroviruses (ERVs)—the remnants of ancient viral infections—comprise a significant 5-8% of the human genome1 3 . Long dismissed as useless "junk DNA," these viral fossils are now emerging as crucial players in human biology, influencing everything from pregnancy to cancer, and inspiring a new frontier of medical therapies.
of human genome consists of ERVs
of human DNA is virus-like sequences
Ancient viral fossils in our DNA
Endogenous retroviruses are the genomic footprints of retroviruses that infected our primate ancestors millions of years ago. Unlike typical viruses, these pathogens performed a unique trick: they infected germline cells (sperm or egg cells) and integrated their genetic code into the host's DNA1 . When this host went on to reproduce, the viral DNA was passed down to the next generation like any other gene, becoming a permanent, inherited fixture in the genome.
Over millennia, most of these viral sequences have accumulated mutations, deletions, and other damage, rendering them unable to produce functional viruses1 6 . They are molecular fossils, but far from inactive ones.
The process of an aggressive virus becoming a quiet genomic passenger unfolds over evolutionary timescales:
An exogenous retrovirus infects a host.
The virus, by chance, infects a germline cell (an egg or sperm cell).
The viral DNA (a provirus) becomes permanently integrated into the cell's chromosomes.
If that cell gives rise to a new organism, the provirus is passed vertically to all the offspring's cells, becoming an ERV.
ERVs possess a complex dual nature. They can be drivers of disease, yet they have also been harnessed by evolution to perform vital biological functions.
The silent viral sequences can be reactivated under certain conditions, and their reawakening is linked to several diseases:
Paradoxically, the same viral invaders have been co-opted to serve essential host functions, a process called exaptation.
For decades, HERV proteins remained invisible to high-resolution imaging, too flexible and unstable to be captured. In a landmark 2025 study, scientists at the La Jolla Institute for Immunology (LJI) achieved a major breakthrough: they decoded the first 3D structure of the HERV-K envelope (Env) protein3 .
The research team faced a significant challenge: the Env protein is "spring-loaded," primed to change shape and fuse with a host cell. To study it, they had to capture it in its delicate pre-fusion state.
Introduced subtle amino acid substitutions to lock the protein into its pre-fusion shape.
Used specific antibodies to anchor and stabilize the structure for imaging.
Flash-frozen structures visualized using cryo-electron microscopy.
Captured the protein in three key states for detailed analysis.
The results, published in Science Advances, revealed a protein with a unique and unexpected architecture3 .
| Retrovirus | Protein Structure | Key Features |
|---|---|---|
| HERV-K | Tall, lean trimer | Novel protein fold distinct from all other known retroviruses |
| HIV | Shorter, squatter trimer | Classic trimer structure seen in many modern viruses |
| SIV | Shorter, squatter trimer | Similar to HIV, reflecting their close evolutionary relationship |
This unique structure explains why the human immune system can recognize HERV-K Env so specifically—it is truly unlike any other protein in the body. The study also successfully used engineered antibodies to detect these Env proteins on immune cells from patients with rheumatoid arthritis and lupus, but not on cells from healthy controls3 . This provides a direct structural basis for understanding how reactivated ERVs could trigger autoimmune responses.
The growing interest in ERVs has driven the development of specialized research tools. The following table details key reagents scientists use to detect and study these elusive elements of our genome.
| Research Tool | Specific Example | Function and Application |
|---|---|---|
| qPCR/PCR Kits | HERV-H Probe qRT-PCR Kit5 | Quantifies HERV DNA levels in human samples; used to study expression changes in cancer and autoimmune disease. |
| Antibody-Based Detection | Anti-HERV-K Env Antibodies3 | Engineered antibodies used to detect viral proteins on cell surfaces; crucial for diagnostic applications and imaging. |
| ELISA Kits | HERV-K10 Protease ELISA Kit8 | Measures concentrations of specific HERV proteins (e.g., protease) in biological fluids like plasma and serum. |
| Stable Cell Lines | NCCIT/KOSOX2 Cells | Engineered teratocarcinoma cell lines with controlled Sox2 expression; used to study how transcription factors reactivate HERVs. |
| Long-Read Sequencing | Oxford Nanopore Technologies4 | Sequences long stretches of DNA (over 10,000 bases), allowing accurate analysis of large, repetitive ERV regions in the genome. |
Modern techniques for identifying and quantifying ERVs in human samples:
How these tools advance our understanding of ERVs:
The revelation of ERV structures and functions is opening up revolutionary new pathways in medicine.
The Dana-Farber study on kidney cancer suggests that reactivated ERVs could be the Achilles' heel for tumors. Doctors might one day harness these viral flags to train the immune system to better recognize and destroy cancer cells, a form of immunotherapy2 .
The unique shape of the HERV-K Env protein provides a perfect target. Antibodies against it could be developed into tools to detect cancer cells or specific autoimmune cells with high precision, enabling earlier and more accurate diagnosis3 .
Understanding how antibodies bind to and neutralize HERV-K Env paves the way for designing new drugs or targeted therapies that could silence detrimental ERV activity in conditions like ALS or lupus3 .
| Disease Area | Potential ERV-Based Application | Current Stage |
|---|---|---|
| Oncology | Immunotherapies that target ERV proteins on cancer cells | Early clinical research2 |
| Autoimmune Diseases | Diagnostics to detect aberrant ERV expression; therapies to block harmful immune responses | Experimental stage3 |
| Neurology | Biomarkers for disease progression in ALS; understanding disease mechanisms | Basic research4 |
| Virology | Understanding how HERV proteins can block modern viruses (e.g., HIV) | Fundamental discovery |
The study of endogenous retroviruses has undergone a profound transformation. Once ignored as genetic junk, they are now recognized as forces that have fundamentally shaped human evolution. They are a testament to the blurred lines between pathogen and partner, demonstrating how our genome dynamically writes its own history, even with a viral pen.
As research continues to unravel the secrets of these ancient guests, one thing is clear: getting to know this viral part of ourselves is not just about understanding our past; it is about unlocking a new future for medicine.