Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses

Abstract

About 8% of our genome is composed of sequences with viral origin, namely human Endogenous Retroviruses (HERVs). HERVs are relics of ancient infections that affected the primates' germ line along the last 100 million of years, and became stable elements at the interface between self and foreign DNA. Intriguingly, HERV co-evolution with the host led to the domestication of activities previously devoted to the retrovirus life cycle, providing novel cellular functions. For example, selected HERV envelope proteins have been coopted for pregnancy-related purposes, and proviral Long Terminal Repeats participate in the transcriptional regulation of various cellular genes. Given the HERV persistence in the host genome and its basal expression in most healthy tissues, it is reasonable that human defenses should prevent HERV-mediated immune activation. Despite this, HERVs and their products (including RNA, cytosolic DNA, and proteins) are still able to modulate and be influenced by the host immune system, fascinatingly suggesting a central role in the evolution and functioning of the human innate immunity. Indeed, HERV sequences had been major contributors in shaping and expanding the interferon network, dispersing inducible genes that have been occasionally domesticated in various mammalian lineages. Also the HERV integration within or near to genes encoding for critical immune factors has been shown to influence their activity, or to be responsible for their polymorphic variation in the human population, such as in the case of an HERV-K(HML10) provirus in the major histocompatibility complex region. In addition, HERV expressed products have been shown to modulate innate immunity effectors, being therefore often related on the one side to inflammatory and autoimmune disorders, while on the other side to the control of excessive immune activation through their immunosuppressive properties. Finally, HERVs have been proposed to establish a protective effect against exogenous infections. The present review summarizes the involvement of HERVs and their products in innate immune responses, describing how their intricate interplay with the first line of human defenses can actively contribute either to the host protection or to his damage, implying a subtle balance between the persistence of HERV expression and the maintenance of a basal immune alert.

Keywords: HERV; autoimmunity; cancer; endogenous retroviruses; evolution; innate immunity; interferon.

Figure 1

Origin and general structure of HERV sequences. Exogenous retroviruses normally infect a specific type of somatic cells, being diffused from a host to new individuals by a horizontal transmission. In the case of HERVs, the ancestral retroviral infection affected the germ line cells: in this way, the proviral sequences have been endogenized and vertically transmitted to all the cells of descendant individuals. HERVs have been so inherited in a Mendelian fashion to the offspring, being fixed in the human population. The general structure of a full-length HERV provirus is represented: the two Long Terminal Repeats (LTRs) are formed during the reverse transcription of the viral RNA genome and flank the gag, pro, pol, and env genes. The primer binding site (PBS) and the polypurine trait (PPT) are located between 5′LTR and gag and between env and 3′LTR, respectively. The viral genes encode for the structural and non-structural proteins found in the viral particle: gag matrix (MA), capsid (CA) and nucleocapsid (NC); pro-pol protease (PR)—reverse transcriptase (RT) and integrase (IN); env surface (SU) and transmembrane (TM) subunits. While in exogenous retroviral infections the integrated provirus is transcribed by the cellular machinery to release new virions, the HERV persistence within the host genome and the action of cellular editing systems led to the accumulation of mutations that often made the proviruses coding-defective and thus unable to produce infectious particles.

Figure 2

HERV role in the regulation and shaping of human gene expression. HERVs can influence the host gene expression at several levels. (a) Integrated DNA sequences can trigger chromosomal rearrangements by non-allelic homologous recombination (1) or disrupt co-localized genes through insertional mutagenesis (2). Moreover, HERV sequences integrated in proximity to a cellular gene can provide alternative promoters or enhance its expression through LTR cis-regulatory elements (3). (b) HERV non-coding RNAs (ncRNAs) can also be able to cis-regulate cellular genes, even through the recruitment of cellular regulators (e.g.: transcription and splicing factors) (4). In addition, HERV ncRNA have been reported to act as “microRNA sponges,” binding and dampening microRNA families responsible for post-transcriptional modifications (5). (c) Finally, some HERV proteins can also regulate genic expression through their interaction with cellular mRNAs and the modulation of their transfer and ribosome occupancy (6).

Figure 3

Sensing of HERV molecules by innate immunity PRRs. Different HERV proteins and nucleic acids (overall indicated in red) can theoretically be detected as PAMPs or DAMPs by cellular sensors localized at the plasmatic or endosomal membranes (transmembrane PRRs or Toll Like Receptors, cyano) or present as soluble factors in the cytosol (cytosolic PRRs, violet). The sensing of these viral molecules by both kind of PRRs triggers a signaling cascade (blue arrows) that leads to the nuclear activation of immune genes encoding for pro-inflammatory effectors, represented by cytokines and type I IFN. The individual PRRs for which a direct interaction with HERV molecules has been reported are marked with an asterisk.

Figure 4

Protective effects exerted by HERVs against exogenous infections. The effects of HERV expression in the impairment of exogenous viruses (red lines) are represented in relation to HIV infection. The various steps of HIV replication are also schematized. Even if HERV expression could theoretically affect any of them, the major implications regard (a) the expression of HERV mRNAs, that can interact by complementarity with HIV RNA, could form dsRNA that is detected as a PAMP by cellular innate immunity sensors; (b) the complementation of HIV structural components with HERV proteins, possibly affecting HIV particles' assembly and release; and (c) the binding of HERV proteins or pseudoparticles to the same cellular receptor, preventing HIV binding and entry. Of note, these effects can be eventually sustained also by the possible upregulation of HERV expression by HIV infection.