Despite having been integrated into genomes of vertebrates for millions of years, ERVs represent an intermediate stage between exogenous viruses and the host genome; it is suggested that immunological tolerance to HERV-derived proteins and peptides is imperfect due to the epigenetic silencing of HERV in the thymus and bone marrow, which prevents deletion of all HERV-specific T and B cells. As evidence of this, immunization of non-human primates with ERV-derived antigens mounted robust polyfunctional cytotoxic T cell response as well as high antibody titers. According to phylogenetic studies, among 30 HERV families existing in the human genome, HERV-K (HML-2) elements which integrated most recently are the most intact and biologically active forms. HERV-K env and HERV-H env, considered to be a new class of tumor-associated antigens, have been found to promote strong cytotoxic T-cell responses in patients with various types of cancers.
On a level of the innate immune sensing of nucleic acids, single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) derived from endogenous retroviruses are recognized by pattern recognition receptors (PRRs).
SsRNAs can be sensed by Toll-like receptors TLR-7 and TLR-8, resulting in secretion of IFN-α by stimulated dendritic cells (DCs) and macrophages, which was observed for ssRNAs derived from HIV-1.
DsRNAs might be one of the most immunogenic nucleic acid pathogen-associated molecular patterns (PAMPs), since they are not found in cells in a normal state. HERV-derived dsRNA can be recognized by TLR-3, RIG-I and MDA5; RIG-I and MDA5 are known to induce a type I IFN response.
When retrotranscribed into DNA, retroviruses can be sensed by cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, leading to the activation of nuclear factor-kappa B (NF-kB) and IFN regulatory factor 3 (IRF3), which in turn trigger a type I IFN response. DsDNA could also be sensed by DNA-dependent activator of IFN-regulatory factors (DAI); DNA:RNA hybrids could be recognized by TLR-9
The recognition of nucleic acids through PRRs provides a very efficient strategy to fight against viral infections, at the same time imposing the host to a risk due to the possibility of recognizing self-nucleic acids and promotion of autoimmunity. Not surprisingly, HERVs have been found to be associated with different autoimmune and inflammatory diseases, such as multiple sclerosis, amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), rheumathoid arthritis (RA), Sjögren syndrome (SS).
On a protein level, a direct interaction between TLRs and certain HERV proteins has been shown. For example, the surface unit of HERV-W Env (also known as Multiple sclerosis-associated retroviral element (MSRV) env) was found to bind to TLR4 and CD14, stimulating the production of pro-inflammatory cytokines including IL-1β, IL-6, and TNFα. HERV-W Env can trigger a maturation process in human dendritic cells, endowing them with the capacity to support a Th1-like type of Th cell differentiation.
Immunological studies have shown some evidence for T cell immune responses against HERVs in HIV-infected individuals. The hypothesis that HIV induces HERV expression in HIV-infected cells led to the proposal that a vaccine targeting HERV antigens could specifically eliminate HIV-infected cells. The potential advantage of this novel approach is that, by using HERV antigens as surrogate markers of HIV-infected cells, it could circumvent the difficulty inherent in directly targeting notoriously diverse and fast-mutating HIV antigens.