by Gertrud U. Rey
Did you know that eight percent of the human genome consists of DNA sequences that are derived from retroviruses? These “endogenous retroviruses” (ERVs) represent concrete evidence for retroviral infections that occurred in our ancestors. Although ERVs have no viral activity, an accumulating body of evidence suggests that they are not entirely dormant and may actually play an important role in stimulating our innate immune response.
Retroviruses owe their name to their replication cycle. Their RNA genome is reverse transcribed into DNA, which is then inserted into the host genome. This mechanism does things in reverse from the order of events in the central genetic dogma, which dictates that DNA should be transcribed into RNA, which is then translated into protein. Once the retrovirus DNA is inserted into the host genome, it is routinely transcribed into RNA along with the host DNA. The newly generated viral RNA can be reverse transcribed into a new DNA copy, which is then re-inserted at a new place in the host genome. Such transpositions of ERVs often compromise the integrity of the host genome because the ERVs can frequently end up integrating in the middle of a gene or in regulatory regions, thereby destroying the gene or altering its transcription. This disruption of genes can be catastrophic, particularly if the damage occurs in germ cells and is transmitted to future generations, or if the genes control tumorigenesis and their disruption leads to cancer.
In contrast to these potential detrimental effects, it turns out that ERVs may also play a beneficial role in the context of our immune system. Using Toll-like receptors, RIG-I, and other similar sensors, sentinel immune cells perceive structurally conserved molecular patterns on invading pathogens as foreign. Even though these sensors should theoretically recognize RNAs transcribed from ERV genes as native molecules because they have been part of our genome for millennia, the ERV RNAs are also perceived as foreign pathogen-associated molecules, and their presence ultimately triggers a cascade of antiviral immune responses. It is therefore not surprising that there are regulatory elements in place to suppress the transcription of ERVs and prevent a perpetual state of antiviral inflammation. What is surprising is that infections with some exogenous viruses cause these regulatory elements to relax their suppressive effects and allow for increased expression of ERVs. For example, influenza virus infection induces the transcriptional repressor TRIM28/KAP1 to undergo a structural change, which eases its inhibitory functions and leads to increased transcription of ERV DNAs. The resulting RNAs are then sensed by RIG-I, which triggers downstream immune events that reduce the replication of influenza virus.
The phenomenon described above likely also happens after infection with other exogenous viruses. For example, in a study aimed at determining the significance of ERV replication during HIV-1 infection, the authors found that highly exposed sex workers who were HIV-negative had disproportionately higher numbers of copies of the endogenous retrovirus-K polymerase gene compared to HIV-1-infected individuals. Although this observation is merely associative, it does suggest that high expression levels of ERV polymerase keeps the immune system on high alert and protects from infections with exogenous HIV-1.
In addition to ERV RNAs, some ERV proteins also appear to modulate the immune system. For example, the human ERV type W envelope protein stimulates Toll-like receptors to induce the expression of antiviral genes by increasing levels of the transcription factor NF-κB. NF-κB in turn promotes production of interferon, which prompts downstream immune signaling complexes to elicit a general antiviral state. In a mechanism called receptor interference, the envelope protein may also directly bind cellular entry receptors, thereby blocking incoming exogenous viruses from binding them, and thus preventing infection with those viruses. Furthermore, ERV envelope proteins may even sequester newly synthesized cell entry receptors and prevent their transport to and integration into the cell membrane, so that incoming exogenous viruses cannot attach to the membrane.
Perhaps the most intriguing link between human ERVs and immunity is their putative involvement in the origins of the adaptive immune response. The human leukocyte antigen (HLA) complex, which helps the immune system differentiate between self and non-self molecules, is by far the most variable region of the human genome, with an ability to recombine and produce an almost unlimited number of variant gene sequences. HLA variability enables the recognition of a wide range of antigens, thus allowing the immune system to have a defensive advantage against a variety of different pathogens. As it happens, about half of the sequences in the HLA region consist of repetitive ERVs, and there is evidence to suggest that the high capacity for variance in the HLA complex evolved from prior recombination and crossover events between different ERV sequences that are homologous to each other.
The literature is replete with evidence for immune responses that are linked to the expression of ERVs; however, I only described a few examples for the sake of brevity. For the most part, the harmful and beneficial effects of ERVs appear to exist in an intricate balance that is undoubtedly the result of the ongoing evolution between viruses and their hosts. It would be interesting to see whether any of the known ERV-triggered immune mechanisms can be exploited for prophylactic and therapeutic applications to prevent and/or treat viral infections and cancer.