Human Endogenous Retroviruses and Diseases

Abstract

Human endogenous retroviruses (HERVs), remnants of ancient retroviral infections, comprise nearly 8% of the human genome and play dual roles in physiological regulation and disease pathogenesis. Once considered genomic "fossils," HERVs are now known to dynamically influence gene expression, immunity, and homeostasis via epigenetic regulation, molecular mimicry, and viral mimicry. Their structural components, including long terminal repeats and conserved viral genes, enable them to act as regulatory elements and potential sources of novel antigens. However, the causal mechanisms linking the dysregulation of HERVs to diseases-the technical challenges in their detection and quantification, as well as their therapeutic potential-remain poorly systematized. This review synthesizes the molecular architecture and evolutionary trajectories of HERVs, emphasizing their tissue-specific expression patterns. We further delineates their pathogenic roles in diseases including cancer, autoimmune conditions, and neurodegenerative disorders. Finally, we discuss emerging strategies targeting HERVs, including epigenetic modulators, immunotherapies, and gene editing, alongside ongoing clinical trials and translational challenges. By integrating molecular insights with clinical perspectives, this work provides a foundational framework for leveraging HERVs as biomarkers and therapeutic targets in precision medicine.

Keywords: human endogenous retroviruses; genetic domestication; transcriptional regulation; molecular mimicry; therapeutic targets.

FIGURE 1

The retroviral infection cycle and provirus formation. The process of retroviral endogenization involves [25, 30]: ① and ② binding and fusion with the target cell, leading to the release of a capsid complex [248] containing RNA copies of the retroviral genome as well as integration factors (not shown). ③ Inside the cells cytoplasm, the viral RTases generate a DNA molecule from the retroviral RNA genome. ④ This DNA is subsequently transported into the nucleus for genomic integration, forming a provirus formation. Transcription and beyond (⑤ and ⑥): The integrated viral DNA (provirus) is recognized by the host cell's transcriptional machinery. This recognition triggers the transcription of the proviral DNA into viral RNA. These transcribed viral RNAs can have two main fates: they can act as the genetic material for the assembly of new retroviral particles, continuing the infectious cycle, or they may insert into and regulate host genes. This dual potential of viral RNAs highlights the complex interplay between retroviruses and their host genomes. Additionally, the diagram also shows the characteristics of HERVs (human endogenous retroviruses) in the upper right, including their presence in the human genome with multiple repetitive sequences, and processes like recombination and insertional events, as well as how they can be activated by LTR to produce functional proteins or HERVs’ peptides, further emphasizing the broader implications of retroviral‐related mechanisms in the context of host genetics. Abbreviations: HERV, human endogenous retroviruse; LTR, long terminal repeat. (Created with bioRender.com, with permission.)

FIGURE 2

Tissue‐specific HERVs RNA expression profile. Detection of distinct HERVs RNA transcripts (numbers indicate identified RNAs) in major human organs, including brain, heart (atrial appendage and left ventricle), skeletal muscle, blood, liver, and testis [29]. Abbreviations: HERV, human endogenous retroviruse; dsRNA, double strand RNA. (Created with bioRender.com, with permission.)

FIGURE 3

The diversity and genomic distribution of HERV components. The structure of HERVs provirus is depicted at the top, consisting of 5′‐LTR, gag, pro, pol, env genes, and 3′‐LTR. HERVs are categorized into three classes (Class I γ‐retroviruses, Class II β‐retroviruses, Class III spumaviruses) based on pol gene characteristics. For each class, associated HERV groups, representative LTRs, and the counts of solitary LTRs/proviruses (presented as [solitary LTRs/proviruses]) are listed. Abbreviations: HERV, human endogenous retroviruse; LTR, long terminal repeat. (Created with bioRender.com, with permission.)

FIGURE 4

HERVs‐induced viral mimicry activates innate immunity. HERVs reactivation in cells may result in a viral mimicry state, causing in bidirectional transcription of ERVs to produce dsRNAs. These dsRNA are exported to the cytoplasm and recognized by PRRs, such as MDA5. MDA5 binding to dsRNA induces the recruitment of TBK1 and aggregation of mitochondrial antiviral signaling protein, which activate IRF7 through phosphorylation. Once activated, IRF7 translocates to the nucleus and induces transcription of IRG‐1. Consequently, type I/III interferons are produced, transported, and secreted into the tumor microenvironment. Secreted type I/III interferons enhance the expression of antigen processing and presentation mechanisms, thereby improving the ability of cancer cells to present antigens. Additionally, blebs from dying cell containing DNA and dsRNA are captured by DCs and also sensitizes cGAS in these cells. These pathways culminate in IFN‐I and IFN‐III production by both cancer and DCs, leading to efficient DCs activation and T cell priming, thus enhancing antitumor responses. Abbreviations: dsRNA, double strand RNA; PRRs, pattern recognition receptors; MDA5, melanoma differentiation‐associated protein 5; TBK1, TANK‐binding kinase 1; IRF7, interferon regulatory factor 7; IRG‐1, interferon‐responsive genes, DCs, dendritic cells; cGAS, cyclic GMP–AMP synthase; IFN‐I, type I interferon; IFN‐III, type III interferon. (Created with bioRender.com, with permission.)

FIGURE 5

Regulation and reactivation mechanisms of HERVs. (A) Regulation mechanisms: HERVs can be suppressed at the level due, to mutations and are controlled by multiple layers of epigenetic regulation, resulting in limited transcriptional activity in most cell types. Key regulatory mechanisms include: (i) targeted heterochromatin formation, initiated by KRAB‐ZFPs binding specifically to HERVs sequences. This binding recruits TRIM28 (KAP1), serving as a scaffold to assemble heterochromatin‐associated proteins and epigenetic modifiers (e.g., histone methyltransferases, histone deacetylases); (ii) establishment of repressive epigenetic marks, primarily DNA methylation, which acts as a primary shield enforcing transcriptional silencing of HERVs loci in adult tissues; (iii) RNA‐mediated targeting also plays a role in inhibiting mammalian ERV. While some of these mechanisms are mainly observed in mice or different types of human transposon they may also play a role in controlling HERVs expression; and (iv) RNA‐mediated silencing pathways. While mechanisms like Dicer‐dependent RNA interference generating small interfering RNAs or antisense transcripts are well established for controlling specific TEs in mice and some human elements, analogous RNA‐directed silencing pathways likely contribute to HERVs regulation in humans. Collectively, these mechanisms tightly constrain HERVs expression. (B) Reactivation mechanism: The repressive state of HERVs can be disrupted by diverse exogenous and endogenous stimuli. Environmental factors (e.g., chemical agents, infectious agents), exogenous viral infections, radiation, aging‐associated processes, exposure to epigenetic‐modifying drugs, cytokines, and mitogens can alter epigenetic landscapes and/or signaling pathways, leading to HERVs reactivation. The revival of HERVs triggers the production of viral transcripts and proteins, which can impact host gene expression by acting as alternative promoters or enhancers. These occurrences could potentially influence crucial biological functions, in hosts or play a role in the onset of certain diseases. Abbreviations: HERV, human endogenous retroviruse; KRAB‐ZFPs, KRAB zinc finger proteins; TEs, transposable elements. (Created with bioRender.com, with permission.)

FIGURE 6

Pathological mechanisms of HERVs. This schematic summarizes the lifecycle of HERVs and their dysregulation in human disease. Ancestral retroviral infection of primates led to integration of viral DNA into the genome, with subsequent stable inheritance. HERVs elements, structured with 5′‐LTR, gag/pro/pol/env genes, and 3′‐LTR, can be reactivated in modern humans. Reactivation drives diverse pathogenic outcomes. Tumor: HERVs RNA/proteins modulate DCs and cytotoxic T‐lymphocyte function, while LTR insertions disrupt oncogene regulation, influencing tumor suppression or progression. Chromosomal recombination at LTRs and demethylation‐driven proto‐oncogene activation further contribute to tumorigenesis, alongside Env‐mediated NF‐κB inhibition and Syncytin‐1‐dependent tumor invasion. Neurodegeneration (e.g., AD): In AD, HERVW activates TLR4 to promote neuroinflammation; HERVK triggers ERK/p38‐mediated apoptosis and cGAS–STING‐driven TDP‐43 aggregation, while HERVW inhibits mitochondrial oxidative stress, intersecting with amyloid plaques and tau pathology. Autoimmunity (e.g., SLE): HERVs nucleic acids activate TLR/cGAS–IFN pathways; Env mimics autoantigens, and LTR demethylation activates T cells. Complement injury via Env–antibody complexes drives systemic manifestations spanning skin, joints, and organs. Abbreviations: HERV, human endogenous retroviruses; LTR, long terminal repeat; DCs, dendritic cells; AD, Alzheimer's disease; TLR4, Toll‐like receptor 4; ERK, extracellular regulated protein kinases; cGAS, cyclic GMP–AMP synthase; STING, stimulator of interferon genes; TDP‐43, TAR DNA binding protein‐43; SLE, systemic lupus erythematosus. (Created with bioRender.com, with permission.)

FIGURE 7

HERVs in cancer diagnosis and treatment. This schematic outlines the clinical utility of HERVs in cancer care. Panel A maps HERVs as prognostic, therapeutic, and diagnostic biomarkers across diverse malignancies (liver, lung, colon, melanoma, glioblastoma, prostate, kidney, breast cancers). Panel B details translation to interventions: CAR‐T therapy: T cells are engineered to express HERV—targeting chimeric antigen receptors, expanded, and reinfused to eradicate HERVs tumor cells. Vaccines: HERVs antigens trigger primary/secondary immune responses, leveraging memory B cells for sustained antitumor immunity. Other treatments: Antiviral agents and DNA methyltransferase inhibitors target HERVs activity to modulate tumor behavior. Collectively, it illustrates HERVs as a nexus for precision oncology, bridging biomarker discovery to therapeutic translation. Abbreviations: HERV, human endogenous retroviruses; CAR‐T, chimeric antigen receptor T cell; DNMTs, DNA methyltransferases. (Created with bioRender.com, with permission.)