Over the course of evolution, several groups of ancient viruses colonized our ancestors’ genomes, leaving thousands of fragments of viral code in modern-day human DNA. The bulk of HERVs integrated during primate evolution. Subsequent mutations in these sequences have rendered older insertions nonfunctional, but some of the younger and more intact sequences from HERVs have been linked to disease.
Around 8 percent of our genetic code stems from HERVs, the bulk of which integrated during primate evolution.
- HERV-K viruses colonized the genomes of ancient primates as early as 55 million years ago (mya). Many of the youngest and most preserved elements, such as those in the HERV-K (HML-2) group, can produce viral proteins and have been linked to ALS.
- The HERV-W group, which invaded the genome starting around 25 mya, was first detected in multiple sclerosis patients and named MS-associated retrovirus (MSRV) for its connection to the myelin-degenerating condition.
- HERV-Fc, the youngest member of the HERV-F viruses, integrated into the genome more than 20 mya and has also been linked with multiple sclerosis.
- HERV-L elements have been detected in all placental mammals, and are thought to have integrated between 100 million and 150 mya. They represent the oldest HERVs in the human genome, are not known to produce any proteins, and so far have not been linked to disease.
Parsing the HERV-disease link
Current research suggests that viral hitchhikers in human DNA may play roles in cancer, inflammation, and neurodegenerative disorders. The mechanisms that underpin these connections between human endogenous retroviruses (HERVs) and disease are just beginning to emerge. Transcription of viral RNA can signal the presence of foreign DNA in cells, triggering defensive immune reactions. Scientists have also proposed that synthesis of the HERV envelope protein—which once enclosed the viral capsid of its retroviral ancestors—exerts pathogenic effects. In other contexts, such as certain cancers, researchers think that the disease state activates HERVs, rather than the other way around.
(1) Activation of viral promoters: Ancient retroviral infections have left viral promoters throughout the human genome. Although our bodies have coopted many of them to drive the expression of our own genes, a lot of those promoters are kept silenced through epigenetic repression. Reactivation of these elements can result in abnormal expression of nearby oncogenes or tumor-suppressor genes. (2) Expression of viral genes: Under some circumstances, such as cancer, many regions of the genome that are normally silenced can awaken. This can activate the transcription of HERVs, causing viral RNA to accumulate in the cytoplasm. According to the “viral mimicry” theory, these molecules alert cellular RNA-sensing pathways to the viral material, triggering an immune response. (3) Translation of viral proteins: Some viral RNAs are translated into proteins, which can be secreted and travel to other cells. It’s unclear what effects these proteins have, but some researchers hypothesize they activate surface receptors and ultimately initiate immune reactions.
HERV proteins in neurodegenerative disease
The discovery of viral proteins in the eroded brains of MS and ALS patients has prompted researchers to investigate the role of HERVs in these diseases. Although this research is becoming more widespread, the mechanisms are still unclear and remain hypothetical.
The HERV-W envelope protein binds toll-like receptor 4 on microglia, triggering the cells to secrete proinflammatory cytokines (1). At the same time, the protein also inhibits these cells from scavenging myelin debris (2), a mechanism important for rebuilding myelin sheaths that are damaged in MS, and prevents oligodendrocyte precursor cells (OPCs)—which normally help remyelinate damaged axons—from maturing (3). Combined, these two pathways create an inflammatory environment that contributes to the development of lesions in the brain, while also impairing the ability of local cells to repair the damage. Researchers haven’t yet discovered what triggers the production of HERV-W in the first place.
Experiments in mice have shown that activation of the most recently integrated HERV in the human genome, known as HERV-K, in specific regions of the nervous system causes motor neuron deterioration. This could explain the neurodegeneration seen in ALS, although it is still unclear exactly how HERV-K is involved. Researchers speculate that the envelope protein of HERV-K causes disruption of the machinery in the nucleolus responsible for producing ribosomes, and this in turn results in cell death (1) .This process is thought to spread from cell to cell—in accordance with the progressive deterioration seen in ALS—through factors that stimulate the production of the viral envelope protein, through the secretion of the protein (2), or possibly through the spread of HERV-K itself, though there is no evidence that the endogenous virus can behave in this way.
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Correction (January 7): The original version of the infographic in this story mistakenly depicted baboons instead of bonobos. The Scientist regrets the error.