Human Endogenous Retroviruses (HERVs): Shaping the Innate Immune Response in Cancers

Abstract

Human Endogenous Retroviruses (HERVs) are accounting for 8% of the human genome. These sequences are remnants from ancient germline infections by exogenous retroviruses. After million years of evolution and multiple integrations, HERVs have acquired many damages rendering them defective. At steady state, HERVs are mostly localized in the heterochromatin and silenced by methylation. Multiple conditions have been described to induce their reactivation, including auto-immune diseases and cancers. HERVs re-expression leads to RNA (simple and double-stranded) and DNA production (by reverse transcription), modulating the innate immune response. Some studies also argue for a role of HERVs in shaping the evolution of innate immunity, notably in the development of the interferon response. However, their exact role in the innate immune response, particularly in cancer, remains to be defined. In this review, we see how HERVs could be key-players in mounting an antitumor immune response. After a brief introduction on HERVs characteristics and biology, we review the different mechanisms by which HERVs can interact with the immune system, with a focus on the innate response. We then discuss the potential impact of HERVs expression on the innate immune response in cancer.

<p>Human Endogenous Retroviruses in Clear Cell Renal Cell Carcinoma: Biological Functions and Clinical Values</p>

“…8,19,21 HERVs may activate the IFN signaling pathway through a viral mimicry process to enhance antitumor immune responses (Figure 2). [36][37][38][39] Epigenetic therapy may increase the sensitivity of cancer patients to ICIs through this process. 37,53 Therefore, DNMTis and ICI combinatory treatment brings hope to cancer patients, especially for patients with poor response to ICIs.…”

“…36,37 The dsRNA and ssRNA can activate its vital sensors including toll-like receptors (TLRs), RLRs retinoic acid-inducible gene I (RIG-I), and melanoma differentiated associated gene 5 (MDA 5), resulting in the expression of type I IFN by activating NF-κB, which can induce IFN-regulatory factor-3 and 7 (IRF-3 and IRF-7). [36][37][38][39] IFNs can increase the expression of MHC type I on tumor cells, which may promote T-cells to recognize tumor cells ( Figure 2). 36,37 Anti-HERV -K gag and env antibodies have been detected in melanoma patients, which proves that HERV-K proteins can activate the humoral immune response, and the HERV-K antigen is the target of CTLs and is presented by HLA-A2 of HLA class I on melanoma cells.…”

“…Notes: Data from these studies. [36][37][38][39] mechanism. There are significant differences between the biological effects of different types of HERVs.…”

Human Endogenous Retrovirus K in Cancer: A Potential Biomarker and Immunotherapeutic Target

“…Further studies exposing human PBMCs to ISD-derived proteins from HERV-K and other retroviruses, such as HIV, showed increases in the expression of numerous immunomodulatory factors, such as IL-10, IL-6 and IL-8, with decreases in the expression of the immune stimulatory factors IL-2 and CXCL9. However, the overall effect of this modulation remains to be clarified [ 81 ]. Furthermore, Env proteins produced by HERV-K mimic the oxygen response element binding protein (OREBP), affecting glutathione peroxidase expression and resulting in increased levels of free radicals in melanoma cells [ 82 ].…”

Endogenous retroviruses transcriptomes in response to four avian pathogenic microorganisms infection in chicken

“…ERVs contain three main coding genes: gag, pol and env, flanked by long terminal repeats (LTRs), which are control regions containing promoters, enhancers and polyadenylation signals [1]. Initially considered as "junk DNA", ERVs have been shown to be involved in many host biological processes such as placental development [3], cancers [4], autoimmune diseases [5], antiviral immunity [6] and reproduction [7]. However, even in human research, the impact of ERVs on human health and disease is still not well understood.…”