How Ancient Infections Fuel Modern Cancers
You are not entirely human—at least not by genetic makeup. A staggering 8% of the human genome consists of ancient viral sequences, remnants of infections that plagued our ancestors millions of years ago 5 . These human endogenous retroviruses (HERVs) were once considered "junk DNA," but science is now revealing their surprising role in one of medicine's most formidable challenges: cancer 9 .
of human genome is viral DNA
Typically silenced and harmless, these sleeping viral giants can reawaken in cancer cells, producing proteins that drive tumor development and progression 1 . From ovarian and breast cancers to glioblastoma and liver carcinoma, HERVs are leaving their fingerprints across multiple cancer types, offering both new explanations for disease and promising new avenues for treatment 5 7 9 . This article explores how these ancient viral remnants influence modern cancer biology and how researchers are working to transform them from foes into allies in the fight against cancer.
HERVs are remnants of ancient viral infections integrated into our genome over millions of years of evolution.
Recent studies reveal HERVs play active roles in cancer development when reactivated.
HERVs are the genetic remnants of ancient retroviral infections that occurred over millions of years of human evolution. When these viruses infected our distant ancestors, some managed to integrate their genetic material into germline cells, allowing this viral DNA to be passed vertically through generations in a Mendelian inheritance pattern 1 . Through this process, what were once foreign pathogens became permanent residents in the human genome.
A complete HERV sequence contains four core genes flanked by two long terminal repeats (LTRs):
Encodes structural components including capsid and matrix proteins
Produces viral protease
Generates reverse transcriptase and integrase enzymes
Codes for the envelope protein, a key surface glycoprotein 1
The LTR regions act as genetic switches, containing promoter and enhancer elements that regulate when and where HERVs become active 1 . While most HERVs have accumulated mutations over time that render them defective, some maintain the ability to produce functional proteins, particularly the more recently integrated HERV-K family 7 .
In healthy cells, HERVs typically remain silent. However, in the abnormal cellular environment of cancer, they can be reactivated through various mechanisms, including epigenetic changes and cellular stress signals 1 9 . Once awakened, HERVs contribute to cancer development and progression through multiple mechanisms:
The envelope protein of HERVs contains an immunosuppressive domain that can dampen anti-tumor immune responses, allowing cancers to evade detection 1 .
HERV LTRs can integrate near cellular oncogenes, acting as alternative promoters that drive their overexpression in tumors 4 .
HERV elements can promote chromosomal rearrangements and other genetic alterations that accelerate cancer progression 9 .
Certain HERV proteins, such as HERV-K's Rec and Np9, can interfere with host cell signaling pathways to promote uncontrolled growth 1 .
HERV activity has been documented in numerous cancers, with distinctive patterns in different tumor types:
| Cancer Type | Key HERV Findings | Clinical Implications |
|---|---|---|
| Ovarian Cancer | Significant upregulation of HERV envelope proteins across histological subtypes 1 | Potential diagnostic biomarker and therapeutic target |
| Glioblastoma | 211 HERVs significantly dysregulated; lower "HERV scores" correlate with poorer survival 7 | Novel prognostic tool and insight into disease pathogenesis |
| Liver Cancer | 206 prognosis-related HERVs identified; TP53 mutation influences HERV expression 4 | New molecular classification system and therapeutic avenues |
| Breast Cancer | HERV envelope proteins present on cancer cells but minimal in normal tissue 1 9 | Opportunity for targeted immunotherapy approaches |
Visual representation of HERV activity levels across different cancer types based on research findings.
In 2025, researchers at La Jolla Institute for Immunology achieved a breakthrough that had eluded scientists for decades: they determined the first three-dimensional structure of a HERV protein—the HERV-K envelope glycoprotein 5 . This landmark study, published in Science Advances, revealed why these proteins had remained invisible for so long and opened new possibilities for diagnostic and therapeutic development.
HERV envelope proteins are inherently unstable—"spring-loaded" to undergo conformational changes that enable viral fusion with host cells. As co-first author Jeremy Shek noted, "You can look at them funny, and they'll unfold" 5 . This instability made them impossible to study with conventional structural biology techniques.
The research team employed several innovative approaches to overcome these challenges:
Introduced subtle amino acid substitutions to "lock" the protein in its pre-fusion state without altering its natural shape.
Developed and characterized specific antibodies that helped stabilize different versions of the viral proteins.
Used this high-resolution imaging technique to capture 3D images of HERV-K Env at key functional moments.
The revealed structure defied expectations. Unlike the shorter, squatter trimers of HIV and SIV, HERV-K Env was tall and lean with a unique protein fold never before seen in other retroviruses 5 . This distinctive architecture explains why antibodies against conventional retroviral proteins don't effectively recognize HERVs and suggests specialized functions that may have evolved to interact with human cellular machinery.
| Structural Feature | Description | Significance |
|---|---|---|
| Overall Architecture | Tall, lean trimer distinct from HIV and SIV | Explains unique functional properties and antibody recognition patterns |
| Subunit Composition | Consists of surface (SU) and transmembrane (TM) subunits | SU determines receptor specificity; TM facilitates membrane fusion |
| Immunosuppressive Domain | Located within the TM subunit | May contribute to immune evasion in cancer cells |
| Structural Dynamics | Spring-loaded mechanism for membrane fusion | Challenging to capture in pre-fusion state for structural studies |
Studying HERVs presents unique challenges due to their repetitive nature, sequence degradation, and integration throughout the genome. Researchers have developed specialized tools and methods to overcome these hurdles:
| Tool/Method | Function | Application Example |
|---|---|---|
| Telescope | Computational tool for locus-specific HERV expression quantification | Identifying dysregulated HERVs in glioblastoma 7 |
| HERV-Fcount | Novel method for HERV quantification based on featureCounts | Analyzing 254 HCC samples to identify prognostic HERVs 4 |
| Cryo-Electron Microscopy | High-resolution imaging technique for protein structure determination | Solving the first 3D structure of HERV-K Env protein 5 |
| GREAT Analysis | Functional prediction tool for genomic regions without annotations | Linking HERV regions to voltage-gated potassium channel genes 7 |
Current status of HERV research methodologies and tools:
As research tools continue to evolve, scientists are focusing on:
The growing understanding of HERV biology is opening exciting new avenues for cancer diagnosis and treatment:
The distinctive presence of HERV proteins on cancer cells but not healthy tissues makes them ideal diagnostic targets. Researchers have already demonstrated that antibodies against HERV-K Env can detect aberrant expression on immune cells from patients with rheumatoid arthritis and lupus, suggesting similar approaches could work for cancer detection 5 .
Several HERV-targeted therapeutic strategies are under investigation:
Antibodies or CAR-T cells designed to recognize HERV envelope proteins could selectively target cancer cells while sparing healthy tissues 5 .
HERV antigens expressed specifically on tumor cells could serve as targets for therapeutic cancer vaccines 9 .
Drugs that reverse epigenetic silencing could reactivate HERV expression in cancer cells, making them more visible to the immune system 4 .
HERV-targeted therapies could be combined with existing immunotherapies to overcome resistance mechanisms 9 .
The first HERV-targeted therapies are already entering clinical trials. A phase I trial is testing the safety of HERV-E-derived peptide autologous T-cell therapy for clear cell renal cell carcinoma, while other HERV-targeting approaches are in earlier stages of development 9 .
Basic science studies identifying HERV roles in cancer and potential therapeutic targets
CompletedConfirming HERV expression patterns and functional significance across cancer types
OngoingCreating antibodies, CAR-T cells, and vaccines targeting HERV proteins
ActiveTesting safety and efficacy of HERV-targeted therapies in patients
Early PhaseIntegration of HERV-targeted approaches into standard cancer care
FutureThe discovery that HERVs play significant roles in cancer represents a paradigm shift in our understanding of both viral evolution and cancer biology. These ancient viral remnants, once considered genetic junk, are now recognized as significant players in tumor development and progression.
As research continues to unravel the complex relationships between HERVs and cancer, the medical potential of these findings grows increasingly promising. The unique features of HERV expression—particularly their presence on cancer cells but not healthy tissues—make them exceptionally attractive targets for the next generation of cancer diagnostics and therapies.
While challenges remain in understanding the precise mechanisms and developing effective interventions, one thing is clear: the hidden viruses in our DNA, once threats to our ancestors, may become unexpected allies in the fight against cancer. As we continue to decode our viral inheritance, we move closer to a future where we can harness these ancient stowaways for modern medicine.
Ancient viral sequences may become powerful tools in cancer treatment