The majority of ERVs that occur in vertebrate genomes are ancient, inactivated by mutation, and have reached genetic fixation in their host species. For these reasons, they are extremely unlikely to have negative effects on their hosts except under unusual circumstances. Nevertheless, it is clear from studies in birds and non-human mammal species including mice, cats and koalas, that younger (i.e., more recently integrated) ERVs can be associated with disease. The number of active ERVs in the genome of mammals is negatively related to their body size suggesting a contribution to the Peto’s paradox through cancer pathogenesis.
This has led researchers to propose a role for ERVs in several forms of human cancer and autoimmune disease, although conclusive evidence is lacking.
In humans, ERVs have been proposed to be involved in multiple sclerosis (MS). A specific association between MS and the ERVWE1, or “syncytin”, gene, which is derived from an ERV insertion, has been reported, along with the presence of an “MS-associated retrovirus” (MSRV), in patients with the disease. Human ERVs (HERVs) have also been implicated in ALS and addiction.
In 2004 it was reported that antibodies to HERVs were found in greater frequency in the sera of people with schizophrenia. Additionally, the cerebrospinal fluid of people with recent onset schizophrenia contained levels of a retroviral marker, reverse transcriptase, four times higher than control subjects.
Researchers continue to look at a possible link between HERVs and schizophrenia, with the additional possibility of a triggering infection inducing schizophrenia. ERVs have been found to be associated to disease not only through disease-causing relations, but also through immunity. The frequency of ERVs in long terminal repeats (LTRs) likely correlates to viral adaptations to take advantage of immunity signaling pathways that promote viral transcription and replication.
A study done in 2016 investigated the benefit of ancient viral DNA integrated into a host through gene regulation networks induced by interferons, a branch of innate immunity. These cytokines are first to respond to viral infection and are also important in immunosurveillance for malignant cells.
ERVs are predicted to act as cis-regulatory elements, but much of the adaptive consequences of this for certain physiological functions is still unknown. There is data that supports the general role of ERVs in the regulation of human interferon response, specifically to interferon-gamma (IFNG).
For example, interferon-stimulated genes were found to be greatly enriched with ERVs bound by signal transducer and activator of transcription (STAT1) and/or Interferon regulatory factor (IRF1) in CD14+ macrophages.
Another idea proposed was that ERVs from the same family played a role in recruiting multiple genes into the same network of regulation. It was found that MER41 elements provided addition redundant regulatory enhancement to the genes located near STAT1 binding sites. When integration of viral DNA occurs in the germ-line, it can give rise to an ERV, which can later become fixed in the gene pool of the host population.