1. Introduction
HERV-K, specifically the subtype HML-2, has been implicated in both normal development and potential disturbances
[1] shaping the cellular landscape; thus, HERV-K (HML-2) contributes to the development of various tissues and organs
[2]. However, disturbances in HERV-K (HML-2) expression have been associated with potential implications and disorders. Aberrant activation or deregulation of HERV-K (HML-2) elements has been observed in different pathological conditions. For instance, in the context of cancer, HERV-K (HML-2) is reactivated in various cancer types, including breast, ovarian, and prostate. Its expression in cancer cells has been linked to promoting cell proliferation, invasiveness, and evasion of immune responses, potentially contributing to tumor progression
[3].
HERV-K (HML-2) has also been associated with autoimmune and inflammatory diseases. Studies have shown that HERV-K (HML-2) transcripts and proteins can activate immune responses, producing inflammatory molecules. This activation may contribute to the development and progression of diseases such as multiple sclerosis (MS), systemic lupus erythematosus, and rheumatoid arthritis
[4][5]. In addition, HERV-K (HML-2) has been associated with neurodegenerative diseases. Increased expression of HERV-K (HML-2) elements has been observed in the brains of individuals with diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and schizophrenia. HERV-K (HML-2) may contribute to neuroinflammation and neuronal dysfunction via mechanisms that remain to be investigated
[1].
Thus, HERV-K (HML-2) proviruses can be classified into two sub-types based on the presence or absence of a specific deletion. Type I proviruses express a protein called Np9, while type II proviruses express the Rec protein, which plays a role in RNA transport
[6][7]. HERV-K Rec can induce viral restriction pathways in early embryonic cells. Polymorphic HERV-K (HML-2) loci with different structures have been identified, and their presence may explain why HERV-K (HML-2) can cause disease in certain individuals
[8][9]. Currently, these loci are gaining attention as potential contributors to complex diseases. There is significant evidence of upregulation of HERV-K (HML-2 subtype)-derived messenger RNA (mRNA) and protein in different types of solid and liquid tumors
[10]. The presence of endogenous retroviruses and the expression of proteins encoded by HERVs in disease states suggest the potential exploration of antiretroviral therapy for managing these conditions. Although direct inhibition of HERVs using HIV-1 RT inhibitors has been reported, until now, there have been no definitive positive clinical trial outcomes with these inhibitors in non-HIV applications. Several ongoing and completed clinical studies are utilizing various combination antiviral products, including RT inhibitors, to treat conditions such as cancer, bone loss, primary biliary cholangitis, Aicardi–Goutières syndrome, psoriasis, multiple sclerosis, and ALS, with some studies focusing on targeting HERV RTs. However, it remains uncertain if the engagement of HERV RT targets can be effectively achieved with these HIV drugs, highlighting the need for more potent and selective HERV RT inhibitors to explore potential therapeutic hypotheses
[11][12].
2. Interaction between Human Endogenous Retrovirus and the Innate Immune System
The interaction between HERV and the innate immune system is crucial in maintaining immune homeostasis and preventing viral infections (
Table 1). The innate immune system employs pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs), which include viral components
[13][14]. Among the PRRs, two prominent families specialize in recognizing nucleic acids: the endosomal PRRs, including toll-like receptors (TLRs), and cytosolic PRRs, including RIG-I-like receptors (RLRs). Activation of TLRs triggers downstream signaling pathways, leading to the production of proinflammatory cytokines and type I interferons (IFNs)
[15]. Similarly, the activation of retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) induces the production of type I IFNs and antiviral responses. It has been observed that specific PRRs, such as TLR-3 and RIG-I, can recognize HERV-derived double-stranded RNA (dsRNA), which activates innate immune responses and induces the production of type I interferons. Type I interferons are crucial in the innate immune response to HERVs. They are produced in response to recognizing HERV-derived single-stranded RNA (ssRNA) or dsRNA by PRRs
[16][17][18]. These interferons inhibit HERV replication and expression, thereby limiting their activity. Additionally, type I interferons are essential in priming and activating the adaptive immune response, which further aids in controlling viral infections
[7][8]. HERV-K (HML-2) has also been associated with autoimmune diseases.
Dysregulation of the innate immune response to HERVs can significantly affect autoimmune diseases. If the innate immune system fails to control HERV expression and production of inflammatory cytokines, it can lead to chronic inflammation, tissue damage, and breakdown of self-tolerance. Some HERV env proteins contain an immunosuppressive domain (ISD) that can modulate immune responses and potentially contribute to immune tolerance, leading to the development of autoimmunity
[19]. The human immune system is not tolerant to HERV-K, and similar findings have been observed in mouse models, where failures of adaptive immunity result in lethal HERV reactivation. These observations suggest that the immune response to HERV-K is unique and may not adhere to the typical tolerance seen with other self-antigens. The innate immune system is the first line of defense against pathogens, including viruses, and plays a crucial role in recognizing and responding to HERVs. The innate immune system is evolutionarily conserved and provides immediate, nonspecific immune responses. Nonetheless, it can reactivate under certain conditions, including viral infections, inflammation, and cancer. While HERVs have immunosuppressive domains, they also contribute to the development of the immune system by providing cis-regulatory elements for gene networks. They are implicated in shaping the IFN-γ network, thereby affecting the immune response. The balance between immune suppression and activation by HERVs is complex and can influence autoimmunity, malignancy, and other disease outcomes
[20][21].
One interesting aspect of HERV-K-specific immune responses is the potential bystander effect. The bystander effect of HERV-K-specific immune responses refers to the possibility that the immune system may target the cells expressing HERV-K proteins and damage the surrounding healthy cells or tissues that do not express HERV-K. This could result in tissue injury, inflammation, or autoimmune reactions. For example, some studies have suggested that HERV-K expression in tumor cells may trigger an immune response that also affects the normal cells in the tumor microenvironment
[22]. Similarly, HERV-K expression in neurons may induce a neuroinflammatory response that harms the neighboring glial cells
[22][23][24]. The mechanisms and consequences of the bystander effect of HERV-K-specific immune responses are not fully understood. They may vary depending on the type and location of the tissue, the level and duration of HERV-K expression, and the nature and specificity of the immune response. However, some possible factors contributing to this phenomenon are as follows: (1) the fusogenic property of the HERV-K envelope protein, which allows it to mediate cell–cell fusion and create syncytia, could facilitate the spread of viral antigens or infection to adjacent cells and increase their susceptibility to immune attack; (2) the cross-reactivity of HERV-K-specific antibodies or T cells with other self-antigens that share structural or functional similarities with HERV-K proteins could lead to a loss of immune tolerance and autoimmunity; (3) the modulation of cytokine production or signaling by HERV-K proteins could affect the inflammatory response and the balance between pro-inflammatory and anti-inflammatory mediators
[23][25].
The cross-reactivity of HERV-K-specific antibodies or T cells with other self-antigens is a significant point to consider. Notably, a recent study that uses bamQuery has provided valuable insights into the immunopeptidome, emphasizing the importance of quantifying RNA expression of tumor-specific antigens, including neoantigens, in both malignant and benign tissues
[26]. The study shows that MHC-I-associated peptides, which can include antigens derived from non-coding genomic regions, may generate tumor-specific antigens. Moreover, the study’s findings indicate that these tumor-specific antigens can originate from multiple discrete genomic regions and are often abundantly expressed in normal tissues.
These observations are particularly relevant when considering HERV-K elements, as they constitute a significant portion of the human genome. While HERV-K elements have been implicated in various diseases, including cancer, the results produced using bamQuery suggest that the transcriptional activity of HERV-K elements may not be confined solely to pathological conditions. Instead, they may be actively expressed in normal tissues, contributing to the pool of potential antigens.
This finding underscores the complexity of HERV-K elements and their regulation, as well as the potential implications for immune responses. The presence of HERV-K-specific antigens in normal tissues raises questions about immune tolerance and the potential for cross-reactivity with HERV-K-related immune responses. As researchers explore the multifaceted roles of HERV-K elements in health and disease, understanding their transcriptional profile in both pathological and non-pathological contexts becomes essential.
The bystander effect of HERV-K-specific immune responses is a complex and intriguing topic that requires further investigation. It may have both beneficial and detrimental effects on human health, depending on the context and outcome of the immune response
[27]. On one hand, it may enhance antitumor immunity and eliminate cancer cells expressing HERV-K. On the other hand, it may cause collateral damage to normal tissues and contribute to chronic inflammation or autoimmunity
[28].
Moreover, researchers can depend on the suppression mechanisms of HERVs, which are multi-layered defenses aimed at silencing or limiting their expression, as outlined in
Table 2. It is important to point out that these mechanisms may exhibit variations across different species, and our comprehension of these processes continues to evolve. Despite their general efficacy in suppressing most HERVs, specific HERV sequences have been co-opted for beneficial purposes during evolution, serving as regulatory elements for the host genome
[29]. Understanding these intricate suppression mechanisms is crucial for unraveling the complex interplay between HERVs and the host immune system, shedding light on potential implications for health and disease.
Table 2. Information about the suppression mechanism of HERVs to better understand the development of disease
[29].
Suppression Mechanism |
Description |
Outcome |
Example |
DNA Methylation |
Chemical modification of DNA by adding a methyl group to cytosine nucleotides. Methylation of ERV sequences, especially regulatory regions, prevents gene expression by blocking access to the transcription machinery. |
Suppression of ERV expression and potential protection against harmful effects of ERV activation. |
Loss of DNA methylation in ERVs can lead to their aberrant activation, resulting in genomic instability and increased risk of diseases like cancer (e.g., hypomethylation-induced activation of oncogenic ERVs in certain cancers). |
Histone Modification |
Modification of histone proteins, which DNA coils around, affecting gene expression. Histone methylation and deacetylation near ERVs maintain a repressive chromatin structure, inhibiting access to ERV sequences by the transcription machinery. |
Silencing of ERVs and prevention of their transcriptional activity. |
Dysregulation of histone modifications can lead to the reactivation of ERVs and contribute to various diseases, including autoimmune disorders (e.g., abnormal histone modifications disrupting ERV silencing and triggering autoimmunity in systemic lupus erythematosus). |
piRNA Pathway |
It involves the production of piRNAs, small non-coding RNA molecules that bind to Piwi proteins. piRNA-Piwi complexes recognize and target ERV transcripts or DNA copies, leading to their degradation and preventing expression. |
Suppression of ERV activity by degradation of ERV transcripts or DNA copies. |
Dysfunction in the piRNA pathway can result in the derepression of ERVs and contribute to developmental abnormalities and diseases like infertility (e.g., mutations in piRNA pathway components leading to loss of ERV silencing and germ cell defects). |
RNA Interference (RNAi) |
Small interfering RNAs (siRNAs) or microRNAs (miRNAs) derived from ERV transcripts can trigger RNAi-mediated degradation of complementary ERV RNA molecules, inhibiting their expression. |
Degradation and inhibition of ERV transcripts prevent their expression. |
Impairment of RNAi machinery can disrupt ERV silencing and potentially contribute to neurodegenerative diseases (e.g., dysregulation of RNAi allowing aberrant expression of neurotoxic ERVs in disorders like amyotrophic lateral sclerosis). |
Transcriptional Repressors |
Transcription factors and other proteins bind to specific DNA sequences to repress ERV transcription. They interfere with transcriptional activators or recruit additional factors to establish a repressive chromatin environment. |
Repression of ERV transcription and prevention of their activation. |
Disruption of transcriptional repressor-mediated suppression can lead to the reactivation of ERVs and contribute to diseases like cancer (e.g., loss of transcriptional repressor binding resulting in aberrant ERV expression and oncogenic transformation). |
Antiviral Defense Pathways |
Activation of antiviral defense pathways, such as interferon signaling, can induce an immune response against ERVs. The immune response produces factors that interfere with viral replication and transcription, suppressing ERV expression. |
Suppression of ERV replication and transcription through immune-mediated mechanisms. |
Dysregulation or failure of antiviral defense pathways can contribute to ERV activation and associated pathologies, including autoimmune diseases (e.g., deficiencies in antiviral defenses leading to ERV activation and autoimmune responses in Aicardi–Goutières syndrome). |
It is theorized that beyond the env protein, additional viral proteins stemming from HERV-K (HML-2), including Rec and Np9, could potentially function as oncoproteins or initiate the production of autoantibodies within the host, thereby playing a role in the progression of diseases. Notably, the env protein has been linked to cell fusion within melanoma, culminating in tumorigenesis. Simultaneously, it is implicated in eliciting immune reactions and fostering the advancement of cancer, along with metastasis, particularly in breast cancer
[32][33]. The Rec and Np9 proteins have shown interactions with disease-related proteins and potential oncogenic properties by modulating gene expression and supporting tumor progression
[34]. Interestingly, HERV-K Rec not only triggers viral restriction pathways in early embryonic cells
[2] but also prevents melanoma from progressing to an invasive stage
[35]. Furthermore, the presence of HERVH-driven genes has been associated with improved survival in lung cancer patients, known as oncoexaptation
[36].
LTRs bordering HERV-K (HML-2) harbor regulatory elements that can impact the expression of host genes. These LTRs exhibit transcription initiation capabilities more frequently than regular promoters, often resulting in reciprocal up- and downregulation of human genes. The effects of LTRs can be twofold, with the ability to drive the expression of tumor suppressor genes that are commonly silenced in tumors while also promoting tumorigenesis through promoter activation and gene expression alterations
[37]. Furthermore, LTRs within HERV-K (HML-2) have been associated with autoimmune disorders, schizophrenia, and chromosomal rearrangements linked to overexpression of oncogenes. Thus, the regulatory functions of LTRs contribute significantly to the potential involvement of HERV-K (HML-2) in various diseases
[38].
In addition, it is crucial to distinguish between active HERV transcription and passive HERV transcription. Passive HERV transcription refers to instances where HERVs are present in a zone of active transcription and are co-transcribed with other genes
[39][40][41]. This distinction becomes particularly relevant in diseases like multiple sclerosis (MS), where the role of HERVs is debated. Some studies suggest that HERVs may serve as passive markers of active transcription zones, while others propose that HERVs could act as triggers of inflammation in MS. This ongoing debate highlights the need for further research to elucidate the precise mechanisms by which HERVs may contribute to the pathogenesis of diseases such as MS
[40][42][43].
Polymorphic integrations of HERV-K (HML-2) within the human genome further contribute to disease susceptibility by influencing viral protein production and regulation of host genes. Specific polymorphic HERV-K (HML-2) loci have been identified with neurologic and immunologic diseases, such as Sjogren’s syndrome, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis
[44]. However, the relationship between polymorphic integrations and diseases needs consistent observation across different studies. While autoimmune disorders have received more attention in the context of polymorphic integrations, investigations into cancer-related polymorphic integrations remain limited.
The role of HERV-K in immune-related diseases is a complex and evolving area of research. It is important to distinguish between aberrant immunity to HERVs and aberrant expression of HERVs to understand their potential causal roles in different diseases. Aberrant immunity to HERVs refers to the immune system’s response to the presence of HERV antigens. As retroviral elements, HERVs can produce various proteins, including envelope and gag proteins, which can be recognized as foreign by the immune system. In some cases, individuals with certain diseases may have an abnormal or dysregulated immune response to HERV antigens. This immune response can lead to inflammation, autoimmunity, or other immune-related problems. However, it is crucial to note that aberrant immunity to HERVs may not be the sole cause of the disease. It could be just one contributing factor among various genetic, environmental, and epigenetic factors.
On the other hand, aberrant expression of HERVs refers to the abnormal activation or upregulation of HERV elements in specific cells or tissues. In certain diseases, such as cancer, autoimmune disorders, and neurological conditions, there is evidence of increased expression of HERVs. The abnormal expression of HERVs can result from various triggers, such as infections, inflammation, or epigenetic changes. This dysregulated expression of HERVs can lead to the production of viral proteins and RNA, which can activate immune responses and contribute to the pathogenesis of the disease.
In some cases, aberrant immunity to HERVs and aberrant expression of HERVs may be interconnected. The immune response to the abnormal expression of HERVs can, in turn, contribute to immune dysregulation and inflammation. This creates a complex feedback loop where HERVs and the immune system interact to influence disease development and progression. Therefore, the same immunity does not cause the same disease despite the presence of HERVs, which highlights the multifactorial nature of these diseases. While HERVs may be involved in various immune-related disorders, their impact can vary depending on other genetic and environmental factors, as well as the specific context of each disease. The interplay between HERVs and the immune system is likely influenced by the overall genetic background of the individual, the state of the immune system, and the presence of other pathogens or triggers. Additionally, the location and timing of HERV expression within the body could also contribute to the diversity of disease manifestations. This hypothesis remains our speculation on a feed-forward mechanism of HERV-K reactivation which may well be relevant, and it should be noted that most inflammatory conditions do not leave a lasting HERV-K reactivated state.
HERVs play a complex role in immune-related diseases, and the interplay between HERV immunity and expression is likely a contributing factor in the pathogenesis of these diseases. However, it is essential to recognize that HERVs are just one piece of the puzzle, and their impact on disease development and progression is influenced by various other factors.
3. HERV-K (HML-2) and Its Link to Viral Infections
This section explores the role of HERV-K (HML-2) reactivation in viral infections to establish a cohesive understanding of its impact on disease development (
Table 3). One of the most prominent examples of HERV-K (HML-2) reactivation is observed in HIV-1 infection
[45]. HIV-1 infection activates the HERV-K (HML-2) loci, leading to the expression of HERV-K proteins
[46]. The exact mechanism of HIV’s direct molecular trigger of HERV-L (HML-2) reactivation is not fully understood, but some studies have shed light on the potential interactions involved.
During HIV infection, the virus produces its regulatory proteins, such as Tat. Tat plays a crucial role in HIV replication by enhancing the transcription of viral genes
[47]. HIV infection induces chronic inflammation, leading to the release of pro-inflammatory cytokines and chemokines. These inflammatory mediators can influence the expression of cellular genes, including those of HERVs. Some HERV elements, like LTRs, contain regulatory regions that respond to inflammatory signals, further promoting their transcription. Moreover, HIV infection can cause alterations in the host cell’s epigenetic landscape. Lastly, HIV’s interaction with host factors, such as cellular transcription factors and chromatin remodeling complexes, might indirectly impact the transcriptional control of HERV-L (HML-2) elements. Interestingly, Li et al. investigated HERV-K (HML-2) activation differences between HIV-1 subtype B and non-subtype B infections (CRF01_AE and CRF07_BC). It was found that subtype B infection upregulated HERV-K (HML-2) gag expression, while non-subtype B infections upregulated HERV-K (HML-2) pol expression. The genetic sequences of HIV-1 subtypes were compared, and differences in gene homology were suggested as a reason for the variations in HERV-K (HML-2) activation. The study also explored the role of HIV-1 Tat protein in HERV-K (HML-2) activation, indicating that Tat from different subtypes may have varying effects. The activation of HERV-K (HML-2) by HIV-1 is a complex process, and further research is needed to understand the underlying mechanisms
[48]. The extent of HERV reactivation can vary between individuals and may depend on the viral load, immune response, and genetic factors. The human genome contains various solo LTRs and HERV sequences that are remnants of ancient viral infections. These viral parasites have successfully evaded elimination by the host. While they may not directly impact host fitness, they serve as valuable sources of regulatory elements and genes that can benefit the host organism. In the case of HIV-1 and other exogenous viruses, the infection activates the HERV-K (HML-2) loci. However, the specific impact of HIV-1 infection on regulatory ERV elements and their influence on gene expression has yet to be fully understood
[46][49].
A recent RNA-seq study found that HIV-1 infection in primary CD4+ T cells activates multiple solo-LTRs from the ERV9 lineage, including LTR12C repeats near antiviral genes. These LTR12C elements are enriched in HIV-1-induced ERVs with transcription start sites. Two HIV-1-responsive LTR12C repeats were identified, acting as promoters for guanylate-binding proteins 2 and 5 (GBP2 and GBP5). These specific LTR12C repeats, unique to greater apes, are associated with heightened cytokine responsiveness in antiviral genes, as seen in comparative studies across primate species
[46][49]. The study also shows that GBP2 and GBP5 decrease the infectiousness of HERV-K (HML-2) pseudoparticles, suggesting that these LTR-induced host factors have already been shown to be useful against other viral pathogens
[50]. These findings illustrate how human cells utilize retroviral remnants to enhance innate immune responses against contemporary viruses. Additionally, another study linked the viral protein Tat, crucial for HIV replication and pathogenesis, to the induction of HERV-K (HML-2) expression. Tat directs cellular transcription machinery to HERV-K (HML-2) long terminal repeats (LTRs), promoting its transcriptional activation. The activation of HERV-K (HML-2) in HIV-infected individuals has spurred interest in targeting it therapeutically, with various approaches explored, including antiretroviral drugs and antibodies
[51][52].
In COVID-19, interferon (IFN) plays a crucial role in the innate immune signaling pathway and host antiviral immunity. The study discussed the activation of human endogenous retroviruses (HERVs), specifically HERV-K (HML-2), with interferon secretion. High expression of HERVs, including HERV-K, has been observed in COVID-19 patients. A study by Guo et al. divided COVID-19 patients into moderate and severe groups and investigated the activation of HERV-K (HML-2) and the expression of interferon-related genes. They observed significant upregulation of HERV-K (HML-2) genes in COVID-19 patients and its association with increased interferon levels, providing insights into the mechanism of interferon production in COVID-19. The study also explored the expression of interferon-related genes in a monkey kidney cell line and suggested using a cell line that can adapt to viral infection and secrete interferon for more effective vaccine production
[53]. The findings contribute to understanding the activation of HERV-K (HML-2) in COVID-19 and its potential implications for immune responses and disease progression. In severe COVID-19 cases, there is an uncontrolled release of pro-inflammatory mediators, leading to inflammation and tissue damage. Immune cells, such as neutrophils and monocytes, contribute to inflammation and tissue damage in COVID-19. Temerozo et al. performed a virome analysis of critically ill COVID-19 patients and identified the activation of endogenous retroelements, including HERV-K. This analysis showed that not only COVID-19 antivirals and anti-inflammatory medications suppressed this expression. HERV-K expression increased in the lower respiratory tract and plasma of severe COVID-19 patients, particularly in those who died, also increased HERV-K expression and is associated with upregulation of pro-inflammatory markers, monocyte activation, and coagulopathy. SARS-CoV-2 experimental infection of human primary monocytes caused the expression of HERV-K to increase; COVID-19 antivirals and anti-inflammatory medications suppressed this expression. These findings link HERV-K to the physiopathology of COVID-19 patients who are critically unwell
[54].
A high-throughput analysis of specific HERV loci in PBMCs was conducted on healthy controls, convalescent individuals, and those retesting positive after recovering from SARS-CoV-2 infection. Differentially expressed HERV loci (deHERV) were identified in individuals exposed to SARS-CoV-2 infection, regardless of the disease’s clinical form. Distinct deHERV loci were found in convalescent individuals and those retesting positive compared to healthy controls. These HERV loci encompassed various HERV groups, including all three classes. This research underscores the connection between HERV expression in PBMCs and the clinical manifestation and prognosis of COVID-19, shedding light on the interplay between HERVs and cellular immunity. It also provides specific transcriptional patterns that may influence COVID-19’s clinical presentation and course of action
[55].
The relationship between human T-cell leukemia virus type 1 (HTLV-1) and HERV-K (HML-2) is of interest in understanding HTLV-1-associated diseases. While HTLV-1 typically remains asymptomatic in most infected individuals, some develop severe conditions like adult T-cell leukemia/lymphoma (ALT) and HTLV-1 HAM/TSP. The mechanisms underlying these diseases remain unclear, but HTLV-1 infection leads to inflammation and neurological symptoms by accumulating infected T cells in the CNS. Damage to uninfected cells may occur due to bystander effects or cross-reactivity of CD8+ T cells with self-antigens in neurons. HERV-K (HML-2) is implicated in this context, given the similarities between HAM/TSP and multiple sclerosis, where HERV expression is associated with disease. Recent studies have shown that the HTLV-1-Tax protein induces the transcription of HERVs
[56]. Screening of HTLV-1-infected individuals for T-cell responses to HERV-derived peptides, specifically focusing on the HERV-K (HML-2) lineage, has provided indirect evidence for the in vivo expression of HERV antigens. The detection of HERV-specific T-cell responses in HTLV-1-infected individuals raises questions about their potential contribution to the pathogenesis of HAM/TSP
[57]. It is hypothesized that HTLV-1 infection induces the expression of HERV antigens, leading to the activation of HERV-specific T-cell responses that could potentially target neurons and other tissues expressing low levels of HERV antigens. Further investigations are necessary to determine the extent of HERV involvement in HTLV-1-associated diseases and their contribution to the observed pathologies.
Interestingly, the expression of HERV-K (HML-2) in hepatitis C virus (HCV) infection has been shown to have implications for liver damage and treatment. The results indicate that factors beyond inflammatory pathways influence HERV-K (HML-2) expression and may be associated with impaired liver function. For instance, increased HERV-K (HML-2) transcript levels are significantly correlated with elevated non-invasive blood markers like ASAT, ALAT, and albumin, which are indicators of liver damage and worsened disease prognosis. They suggested the potential inclusion of reverse transcriptase inhibitors, such as Raltegravir, in HCV antiviral therapy to improve treatment success. These inhibitors have proven effective in treating retroviral diseases like HIV and have shown the ability to inhibit human endogenous retroviruses
[58]. Similar associations between HERV activation and disease development have been observed in conditions such as multiple sclerosis (MS), triggered by Epstein–Barr virus (EBV) infection. In EBV-immortalized lymphoblastoid B cell lines (LCL) from MS-affected individuals, increased expression of HERV-K loci and other genes associated with relapses was observed, indicating a potential role of HERVs in MS pathogenesis
[59]. These findings underscore the importance of understanding the role of HERVs in viral infections and their potential as biomarkers or therapeutic targets in related diseases (
Table 3). Apart from direct molecular triggers, inflammation, and cellular senescence can also induce HERV-K (HML-2) reactivation. Cytokine-induced senescence is a common feature in many viral infections and could be of particular importance in viral-associated diseases like HCV
[23]. Studies have shown that HERV-K (HML-2) is maintained after HCV viral clearance and is associated with the fibrosis score, suggesting its potential role in liver damage and disease progression.
Overall, the activation of endogenous retroviruses, such as HERV-K (HML-2), in the context of viral infections like HIV, HTLV-1, and COVID-19, highlights the intricate relationship between viral pathogens and the human genome. While these viral remnants have the potential to modulate immune responses and contribute to disease pathogenesis, they also represent a fascinating evolutionary record of ancient viral infections. They may offer opportunities for the development of novel therapeutic strategies.
4. Exploring the Expression of HML-2 in Tumors
Earlier research has indicated that human endogenous retrovirus (HERV) can induce the proliferation of tumor cells and evade apoptosis, representing a significant contributing factor to tumor advancement. HML-2 expression has been detected in various types of tumors, and its presence has been associated with prognostic features and unfavorable outcomes in these cancers (
Table 4). HERV-K (HML-2) colonized the human germ line and is closely related to the mouse mammary tumor virus (MMTV) that causes breast cancer in mice
[60]. In breast cancer, the overexpression of HML-2 is linked to aggressive subtypes and the spread of cancer cells to lymph nodes. Similarly, HML-2 is upregulated in basal-like breast cancers, especially in triple-negative breast cancer cases
[61][62]. Notably, recent research has identified shared CD8+ T-cell epitopes derived from cancer-associated HERVs, including those from the HML-2 family, in solid tumors
[63]. These epitopes have shown immunogenicity and the ability to induce high-avidity CD8+ T-cell responses. This discovery holds significant promise for the development of cancer vaccines or T-cell-based immunotherapies, particularly in tumors with high expression of HERVs from the HML-2 family, such as triple-negative breast cancer cases in prostate cancer, HML-2 expression is higher than in benign tissues, and it correlates with tumor development and metastasis
[54][64]. Melanoma also exhibits HML-2 expression, associated with tumor progression and decreased survival
[65]. Regarding HERVs in leukemia, recent research demonstrated the expression of HML-2-derived HERVs in leukemic stem cells. It highlighted the presence of HERV-specific CD8+ T cells in the bone marrow of leukemia patients. Further contributing to the development of a HERV signature that can be used to characterize leukemic stem cells
[66]. In lung cancer, HML-2 can be detected in blood samples of patients, although its levels do not correlate with the stage of the disease
[67]. Additionally, hepatocellular carcinoma and colorectal cancer display increased HML-2 expression, linked to poorer overall survival. Furthermore, HML-2 is observed in leukemia and lymphoma, suggesting its potential involvement in hematological malignancies.
HERV-K sequences are highly expressed in teratocarcinoma cells and have been associated with leukemia and germ cell tumors
[68][69]. Recent advancements in PCR-based target enrichment sequencing protocols have provided valuable information about the role of HERV-K (HML-2) in different cancers. The detection of HML-2 mRNA in the blood shows promise as a particular disease marker for multiple cancers
[70]. For instance, in breast cancer, HML-2 env mRNA levels were significantly elevated in patients’ blood, and chemotherapy was found to reduce its expression. Notably, Wang-Johanning et al. discovered that serum HML-2 mRNA was upregulated in women with early-stage ductal carcinoma in situ (DCIS), indicating its potential as an early marker for metastatic risk. Prostate-specific antigen (PSA) is currently used for prostate cancer screening, but alternative markers are sought due to its limitations
[71]. Wallace et al. explored the detection of HML-2 in peripheral blood mononuclear cells (PBMCs) as a combined test. They observed significant upregulation of HML-2 gag mRNA in prostate cancer cases compared to controls, with its levels associated with higher odds of diagnosis. Interestingly, HML-2 gag exhibited better predictive ability in older men compared to PSA
[72].
Regarding the functional role of HML-2 in tumor progression, its expression has been associated with disease advancement in various cancer types, suggesting a functional role rather than a mere consequence of carcinogenesis. Breast cancer, pancreatic cancer, leukemia, and teratocarcinoma cells have been discovered to enhance cell proliferation in response to HML-2 proteins such as env and Np9. Inhibiting HML-2 env in breast cancer reduced cell invasion and migration by affecting the Ras/Raf/MEK/ERK signaling cascade. Similarly, cell migration in assays for wound healing was impacted by the modification of Np9 expression in teratocarcinoma cells
[73][74]. Furthermore, HML-2 Env, which contains a potential immunosuppressive domain, may possess immunomodulatory capacity as a non-self-epitope. Treatment with HML-2 viral particles or a recombinant peptide derived from the transmembrane subunit inhibited immune cell proliferation and altered cytokine secretion, including an increase in immunosuppressive interleukin-10 (IL-10). This suggests that HML-2 env might interact with tumor-infiltrating immune cells, contributing to the development of an immunosuppressive tumor microenvironment. The specific mechanisms of interaction and signaling pathways involved require further investigation
[75][76].
Additionally, it has been discovered that the expression of HML-2 is a distinct marker for embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), being quickly muted following differentiation. Due to this property, HML-2 has been investigated as a marker for cancer stem cells (CSCs) or tumor-initiating cells. When melanoma cells were grown in stem-cell media, HML-2 transcription increased, correlated with improved stemness traits and the proliferation of putative CSC populations. HML-2 suppression stopped the CD133+ CSC population from growing. Furthermore, stem/progenitor cell counts in samples from leukemia patients were linked with Np9 protein levels
[76][77]. It is important to acknowledge that although HML-2 proteins have the potential to play functional roles in tumor progression, further research is required to fully comprehend the underlying molecular mechanisms and their implications for cancer development and treatment. HERV-K proteins are characterized as neoantigens, which are tumor-specific antigens expressed in various cancer types. They can trigger both innate and adaptive immune responses. Innate immunity activates B and T cells to produce antibodies and cytotoxic T-cell responses
[5]. Studies have shown that antibodies targeting HERV-K can inhibit cancer growth in vitro and in animal models. HERV-K expression has been studied as a biomarker for cancer screening and a target for immunotherapy. Several studies have demonstrated immune responses, including the production of anti-HERV-K antibodies and HERV-K-specific CD8 T-cell responses, against HERV-K in these types of cancer. In melanoma, cytotoxic CD8 T-cell responses against HERV-K have been observed, and the prevalence of anti-HERV-K antibodies has been found to differ significantly between melanoma patients and healthy individuals
[78]. In prostate cancer, HERV-K expression has been associated with disease progression and poorer survival outcomes
[79]. Similarly, in breast cancer, HERV-K expression has been correlated with a negative prognosis and has been suggested as a potential prognostic biomarker. Additionally, HERV-K antigens have been investigated as potential targets for cancer immunotherapy, including dendritic vaccines, CAR-T cells, and recombinant vaccines
[80]. Unlike conventional tumor antigens, HERV-K (HML-2) exhibits a distinct complexity, composed of protein and nucleotide components, making it a versatile antigen. This intriguing combination endows HERV-K (HML-2) with diverse characteristics, including cell surface presentation, viral particle formation, CD8 T-cell targetability, and the ability to stimulate innate immune responses. These features have sparked interest in exploring the potential of HERV-K (HML-2) as a novel immunotherapeutic target for cancer treatment.
Table 4. Main ideas of HERV-K (HML-2) as a target in cancer.
Type of Cancer |
Key Ideas of HERV-K (HML-2) as a Biomarker and/or a Target in Cancer |
Breast Cancer |
-HERV-K (HML-2) expression correlates with disease progression, lymph node metastasis, and reduced overall survival. -HERV-K env protein shows promise as a therapeutic target in immune-mediated therapies. Anti-HERV-K monoclonal antibodies (mAbs) and HERV-K env-specific CAR-T cells have effectively reduced tumor growth [17][81]. |
Hepatocellular Carcinoma |
-HERV-K (HML-2) expression is an independent prognostic indicator of overall survival. -The HERV-K env protein is associated with cirrhosis, tumor differentiation, and staging [17]. |
Hodgkin’s Lymphoma |
-Evidence suggests HERV-K expression in patients with Hodgkin’s lymphoma, with a significant drop in titer levels after appropriate treatment [17]. |
Melanoma |
-HERV-K (HML-2) expression has been observed in melanoma cells, and HERV-K-specific CD8+ T-cell responses have shown specificity to HERV-epitope-presenting tumor cells [14]. -The HERV-K env protein is a potential therapeutic target. |
Prostate cancer |
-HERVs could potentially serve as diagnostic or prognostic biomarkers for prostate cancer due to antibody response [18][82]. |
Germ Cell Tumors |
-The expression of HML-2 and its co-correlation with other genes, such as proline dehydrogenase (PRODH), suggests its involvement in tumorigenesis, particularly in germ cell tumors [83]. The epigenetic regulation of HML-2 expression and its potential role as a cis-regulatory element highlights the possibility of targeting HML-2 to regulate tumor-specific gene expression [19][84]. |
Ovarian Cancer |
-Detection of antibody response. The immune system can recognize the abnormal expression or activation of HERVs in ovarian cancer cells through TLR3 and MAVS, leading to the production of type I interferon (IFN) and triggering apoptosis [20]. |
Pancreatic Cancer |
-HML-2 env has been shown to promote proliferation [21][85]. |
Hepatocellular Cancer |
-HERV-K (HML-2) expression in colorectal cancer is correlated with clinical parameters such as cirrhosis, tumor differentiation, and TNM stage. Additionally, high expression of HERV-K (HML-2) is associated with poorer overall survival in colorectal cancer patients, indicating its potential as a prognostic biomarker for this type of cancer [22]. |
Lung Cancer |
-The activation of B cell and antibody responses against these HERV antigens may play a significant role in anti-tumor immunity and the response to immunotherapy in lung cancer patients–HERV has a potential biomarker [23][24][86]. |
Colon Cancer |
-HERV-K (HML-2) expression has been implicated in colon cancer progression. Studies have shown that increased HERV-K (HML-2) expression correlates with disease progression, lymph node metastasis, and reduced overall survival in patients with colon cancer. -Targeting HERV-K (HML-2) proteins, such as the env protein, may hold promise as a therapeutic strategy in colon cancer [25]. |
Colorectal Cancer |
Differentially expressed HERV-K (HML-2) loci in colorectal cancer were identified, with a concentration in immune response signaling pathways, indicating the potential impact of HERV-K on the tumor-associated immune response. These findings suggest that HERV-K could serve as a screening tumor marker and a target for tumor immunotherapy in colorectal cancer [26]. |
Acute Myeloid leukemia |
A study utilizing whole-genome sequencing and read mapping identified a statistical correlation between AML and 101 HERV-K (HML-2) transposable element insertion polymorphisms (TIPs), indicating a potential relationship between HERV-K (HML-2) and AML [27]. |
Glioblastoma |
HERV expression was associated with a cancer stem cell phenotype and poor patient outcomes. Inhibiting HERV-K (HML-2) expression with antiretroviral drugs can reduce tumor viability and pluripotency [87]. |
Renal Carcinoma |
HERV-K (HERV-K env) was identified as a novel tumor antigen and prognostic indicator. Higher HERV-K (HML-2) env protein levels are associated with better disease-specific survival rates, suggesting potential as a prognostic marker [88]. |
Similarly, HERV-K (HML-2) influenced tumorigenic characteristics in colorectal cancer. Knocking out the HERV-K env gene using the CRISPR-Cas9 system in colorectal cancer cells significantly reduced cell proliferation, migration, and tumor colonization. This effect was related to the downregulation of nuclear protein-1 (NUPR1), which plays a crucial role in cancer cell proliferation and migration. Inhibition of HERV-K (HML-2) expression decreased reactive oxygen species levels, further affecting cancer cell behavior
[90]. In the case of ovarian cancer, the CRISPR-Cas9 knockout of the HERV-K (HML-2) env gene affected tumorigenic characteristics in different ways depending on the ovarian cancer cell line. Knocking out the gene led to cell proliferation, migration, and invasion changes by affecting the expression of RB and Cyclin B1 proteins, critical regulators of cell cycle progression and tumor growth
[91].
In renal cell carcinoma, the envelope protein of HERV-K (HERV-K env) was identified as a novel tumor antigen and a prognostic indicator. Its expression was significantly elevated in clear renal cell carcinoma (ccRCC) compared to other subtypes. Patients with higher HERV-K (HML-2) env protein levels had better disease-specific survival rates, suggesting its potential as a prognostic marker in this type of cancer
[92].
The findings from these studies highlight the significant role of HERV-K (HML-2) in various types of cancer, influencing critical aspects such as stem cell characteristics, tumorigenic behaviors, and patient prognosis. The reactivation of these endogenous retroviruses presents exciting new opportunities in cancer research, including potential applications in diagnostics, therapeutic targeting, and prognostic indicators. However, to harness the full potential of HERV-K as a clinical tool, further research is essential to comprehensively understand its underlying mechanisms and clinical implications in cancer development and treatment. To optimize HERV-K as a specific target for different malignancies, more in-depth characterization of HERV-K expression patterns in various cancer types is required. In developing therapeutic strategies, it is crucial to consider how HERV-K contributes to normal development and whether its targeting could disrupt essential cellular processes. This requires a thorough understanding of the functional roles of HERV-K in healthy cells and tissues. By carefully assessing its impact on normal physiology, researchers can design therapies explicitly targeting cancer cells while sparing healthy cells. To validate the effectiveness of HERV-K targeting in cancer management, it is imperative to conduct comprehensive in vitro models and robust clinical research. In vitro studies will provide valuable insights into the mechanisms of HERV-K action and its interactions with various signaling pathways, aiding in the development of targeted therapeutics. Clinical trials will be crucial to evaluate the safety, efficacy, and potential side effects of HERV-K-based therapies in real-world settings.