Human Endogenous Retroviruses as Gene Expression Regulators: Insights from Animal Models into Human Diseases

Abstract

The human genome contains many retroviral elements called human endogenous retroviruses (HERVs), resulting from the integration of retroviruses throughout evolution. HERVs once were considered inactive junk because they are not replication-competent, primarily localized in the heterochromatin, and silenced by methylation. But HERVs are now clearly shown to actively regulate gene expression in various physiological and pathological conditions such as developmental processes, immune regulation, cancers, autoimmune diseases, and neurological disorders. Recent studies report that HERVs are activated in patients suffering from coronavirus disease 2019 (COVID-19), the current pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. In this review, we describe internal and external factors that influence HERV activities. We also present evidence showing the gene regulatory activity of HERV LTRs (long terminal repeats) in model organisms such as mice, rats, zebrafish, and invertebrate models of worms and flies. Finally, we discuss several molecular and cellular pathways involving various transcription factors and receptors, through which HERVs affect downstream cellular and physiological events such as epigenetic modifications, calcium influx, protein phosphorylation, and cytokine release. Understanding how HERVs participate in various physiological and pathological processes will help develop a strategy to generate effective therapeutic approaches targeting HERVs.

Keywords: COVID-19; cancer; human endogenous retrovirus; neurological disease; syncytin-1; toll-like receptor.

Fig. 1. Animal models used in HERV studies.

HERV expression is required for normal development and its abnormal activation can result in several cancers and neurological diseases. Transgenic animals are generated by microinjection of DNA fragments or plasmids harboring HERV LTR, env, and rec genes into the pronuclei of fertilized eggs of vertebrate models of zebrafish, rats, and mice, or into the gonad of the worm C. elegans. Regulatory elements of HERV LTRs act as promoters/enhancers in many animal models and can affect the expression of the nearby gene or reporter. Some model animals expressing HERV env and rec genes show the shared features with human diseases such as cancers, ALS, and type-1 diabetes. Transgenic fruit flies expressing human TDP-43 (hTDP-43), which forms pathological aggregates in various neurodegenerative diseases such as ALS, FTD, and AD, activates Drosophila ERV gypsy, that is structurally related to HERV-K, and their neurons degenerate. Genetically modified pigs suppressing porcine endogenous retroviruses (PERVs), which are still infectious, different from HERVs, are developed to overcome a potential risk of cross-species transmission of PERVs in xenotransplantation. Tumor xenograft animal models also show that HERV elements increase cancer cell proliferation and tumor growth. Animal models can be used to analyze the role of HERV function in vivo and help better understand how they are involved in the disease process. Figure was created with BioRender.com.