Endogenous retroviruses (ERVs) are remnants of ancient viral infections that have become permanent features of the host genome. These sequences are essentially “fossilized” viral DNA, inherited through generations after successful integration into the reproductive cells of an ancestor millions of years ago. ERVs are remarkably prevalent, comprising an estimated 5% to 8% of the entire human genetic blueprint. They are distinct from active, exogenous retroviruses because they are passed vertically from parent to offspring.
The Process of Genomic Integration
The journey from an active, exogenous retrovirus to a permanent endogenous retrovirus begins with a rare infection event in the host’s germline cells, specifically the sperm or egg. An exogenous retrovirus uses its reverse transcriptase enzyme to convert its RNA genome into a DNA copy, which then integrates into the host cell’s nuclear DNA, forming a provirus. If this integration occurs in a somatic cell, the provirus is limited to that individual.
However, if the integration happens in a germline cell, the provirus is passed down to the next generation as an inherited trait. For an ERV to become fixed and shared across an entire species, the original integration event must have occurred millions of years ago in a common ancestor.
Mechanisms of Viral Silencing
The host genome has developed sophisticated systems to keep ancient viral sequences dormant. Over millions of years, ERV sequences accumulate inactivating mutations, which progressively decay the viral genes required for replication. The original retroviral genome contains genes like gag, pol, and env, which encode for structural proteins, reverse transcriptase, and the viral envelope, respectively. Mutations within these coding sequences introduce premature stop codons or frameshifts, rendering the viral machinery non-functional.
Beyond simple mutation, the host cell employs powerful epigenetic mechanisms to physically repress the expression of these sequences. The primary method is DNA methylation, where methyl groups are added to the cytosine bases within the ERV’s DNA, particularly in the long terminal repeats (LTRs) that function as promoters. This methylation locks the DNA into a condensed, inactive state known as heterochromatin, physically blocking the cell’s machinery from reading the viral genes.
The modification of histone proteins also plays a major role in ERV silencing. Specific histone modifications, such as the trimethylation of lysine 9 on histone H3 (H3K9me3), are associated with a repressive chromatin structure. Specialized protein complexes, including those involving KRAB-zinc finger proteins (KRAB-ZFPs), recognize and bind to ERV sequences, recruiting enzymes that apply these repressive histone marks.
Essential Evolutionary Contributions
Despite their viral origin, some ERV elements have been co-opted, or “domesticated,” by the host to perform beneficial functions. The most widely cited example is the syncytin gene, which is derived from an ancient retroviral envelope (env) gene. This gene is expressed specifically in the placenta and is directly responsible for the formation of the syncytiotrophoblast layer.
The syncytiotrophoblast is a multinucleated cell layer that forms the barrier between maternal and fetal blood, facilitating gas and nutrient exchange. The protein encoded by syncytin retains the fusogenic ability of the original viral envelope protein, allowing it to mediate the fusion of individual placental cells into this single, continuous layer. This co-option is thought to have been a major driving force in the evolution of the placental structure in mammals.
In addition to coding for functional proteins, the LTR sequences that flank ERVs can be utilized by the host as alternative promoters or enhancers. These regulatory sequences contain binding sites for host transcription factors, which can influence the expression of neighboring host genes. The insertion of an ERV near a host gene can therefore provide a new regulatory switch, allowing for tissue-specific or developmental-stage-specific expression patterns.
Associations with Human Disease
While most ERVs are silenced, the loss of this tight regulation can lead to the inappropriate expression of viral elements, which is often observed in disease states. The aberrant activation of ERV sequences has been linked to the initiation or progression of certain autoimmune disorders and cancers. For instance, increased expression of specific human endogenous retroviruses, such as HERV-W and HERV-K, has been consistently reported in patients with Multiple Sclerosis (MS).
This inappropriate expression can trigger an immune response, where the host’s system recognizes the viral proteins or RNA as foreign, leading to chronic inflammation and tissue damage. In the context of cancer, ERV activation is frequently observed in tumor cells. In some cases, the ERV’s LTR acts as an alternative promoter, driving the expression of a nearby oncogene and contributing to tumor growth. These associations are complex, and ERV expression is generally considered a correlate or contributor rather than the sole cause of disease development.