Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions
Abstract
:1. Retrovirus: Human Endogenous Retroviruses (HERVs)
2. The Disease-Inducing Potential of HERV-K (HML-2)
2.1. Interaction between HERV and the Innate Immune System
Aspect | Description | Example |
---|---|---|
Pattern Recognition Receptors (PRRs) | Innate immune system receptors detect pathogen-associated molecular patterns (PAMPs), including viral components. Among them, two prominent families specialize in the recognition of nucleic acids: endosomal PRRs (the TLR family) and cytosolic PRRs (including RIG-I-like receptors (RLRs). The toll-like receptors’ (TLRs) activation triggers downstream signaling pathways, producing proinflammatory cytokines and type I interferons (IFNs). The activation of retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) induces type I IFN production and antiviral responses. | TLR-3 and RIG-I are PRRs recognizing HERV-derived dsRNA, activating innate immune responses, and inducing type I interferon production [63]. |
Interferon Response | The innate immune recognition of ERVs results in the production of type I interferons (IFNs). Type I IFNs inhibit ERV replication and expression and play a crucial role in priming and activating the adaptive immune response. | HERV-derived ssRNA or dsRNA can trigger the production of type I IFNs, which enhance the immune response and limit HERV replication [63]. |
Epigenetic Regulation | Activation of innate immune signaling pathways induces changes in chromatin structure and DNA methylation, leading to transcriptional repression of ERVs and limitation of their activity. | Histone H3 trimethylation (H3K9me3) and DNA methylation contribute to the epigenetic silencing of HERVs and their control in differentiated cells [63]. |
ERV Suppression and Autoimmunity | Dysregulation of innate immune response to ERVs can contribute to autoimmune diseases. Failure to control ERV expression and production of inflammatory cytokines can lead to chronic inflammation, tissue damage, and breakdown of self-tolerance. | The transmembrane subunit of the HERV envelope protein contains an immunosuppressive domain (ISD) that can modulate immune responses and contribute to immune tolerance [63]. |
2.2. HERV-K (HML-2) and Its Link to Viral Infections
2.3. Exploring the Expression of HML-2 in Tumors
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 [60,122]. |
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 [60]. |
Hodgkin’s Lymphoma | -Evidence suggests HERV-K expression in patients with Hodgkin’s lymphoma, with a significant drop in titer levels after appropriate treatment [60]. |
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 [119]. -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 [61,123]. |
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 [124]. 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 [62,125]. |
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 [63]. |
Pancreatic Cancer | -HML-2 env has been shown to promote proliferation [64,126]. |
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 [65]. |
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 [66,67,127]. |
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 [68]. |
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 [69]. |
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 [70]. |
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 [128]. |
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 [129]. |
3. Exploring Therapeutic Opportunities: Potential Drug Targets of HERV-K (HML-2) and Existing Medication
3.1. Potential Use of Antiviral Drugs
3.2. HERV-Based Therapies for Cancer
4. Exploring HERV-K (HML-2) to Unravel Disease Mechanisms for Improved Treatment Strategies: In Vitro and In Silico Approaches
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Vargiu, L.; Rodriguez-Tomé, P.; Sperber, G.O.; Cadeddu, M.; Grandi, N.; Blikstad, V.; Tramontano, E.; Blomberg, J. Classification and Characterization of Human Endogenous Retroviruses; Mosaic Forms are Common. Retrovirology 2016, 13, 7. [Google Scholar] [CrossRef] [PubMed]
- Grandi, N.; Cadeddu, M.; Blomberg, J.; Tramontano, E. Contribution of Type W Human Endogenous Retroviruses to the Human Genome: Characterization of HERV-W Proviral Insertions and Processed Pseudogenes. Retrovirology 2016, 13, 67. [Google Scholar] [CrossRef] [PubMed]
- Belshaw, R.; Pereira, V.; Katzourakis, A.; Talbot, G.; Pačes, J.; Burt, A.; Tristem, M. Long-Term Reinfection of the Human Genome by Endogenous Retroviruses. Proc. Natl. Acad. Sci. USA 2004, 101, 4894–4899. [Google Scholar] [CrossRef] [PubMed]
- Posso-Osorio, I.; Tobón, G.J.; Cañas, C.A. Human Endogenous Retroviruses (HERV) and Non-HERV Viruses Incorporated into the Human Genome and Their Role in the Development of Autoimmune Diseases. J. Transl. Autoimmun. 2021, 4, 100137. [Google Scholar] [CrossRef] [PubMed]
- Martin, M.A.; Bryan, T.; Rasheed, S.; Khan, A.S. Identification and Cloning of Endogenous Retroviral Sequences Present in Human DNA. Proc. Natl. Acad. Sci. USA 1981, 78, 4892–4896. [Google Scholar] [CrossRef] [PubMed]
- Lander, E.S.; Linton, L.M.; Birren, B.; Nusbaum, C.; Zody, M.C.; Baldwin, J.; Devon, K.; Dewar, K.; Doyle, M.; FitzHugh, W.; et al. Initial Sequencing and Analysis of the Human Genome. Nature 2001, 409, 860–921. [Google Scholar] [CrossRef] [PubMed]
- Tönjes, R.R.; Löwer, R.; Boller, K.; Denner, J.; Hasenmaier, B.; Kirsch, H.; König, H.; Korbmacher, C.; Limbach, C.; Lugert, R.; et al. HERV-K: The Biologically Most Active Human Endogenous Retrovirus Family. J. Acquir. Immune. Defic. Syndr. Hum. Retrovirol. 1996, 13, S261–S267. [Google Scholar] [CrossRef]
- Young, G.R.; Stoye, J.P.; Kassiotis, G. Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis. BioEssays 2013, 35, 794–803. [Google Scholar] [CrossRef]
- Bannert, N.; Kurth, R. The Evolutionary Dynamics of Human Endogenous Retroviral Families. Annu. Rev. Genom. Hum. Genet. 2006, 7, 149–173. [Google Scholar] [CrossRef]
- Hohn, O.; Hanke, K.; Bannert, N. HERV-K(HML-2), The Best Preserved Family of HERVs: Endogenization, Expression, and Implications in Health and Disease. Front. Oncol. 2013, 3, 246. [Google Scholar] [CrossRef]
- Subramanian, R.P.; Wildschutte, J.H.; Russo, C.; Coffin, J.M. Identification, Characterization, and Comparative Genomic Distribution of the HERV-K (HML-2) Group of Human Endogenous Retroviruses. Retrovirology 2011, 8, 90. [Google Scholar] [CrossRef]
- Dewannieux, M.; Blaise, S.; Heidmann, T. Identification of a Functional Envelope Protein from the HERV-K Family of Human Endogenous Retroviruses. J. Virol. 2005, 79, 15573–15577. [Google Scholar] [CrossRef] [PubMed]
- Ono, M. Molecular Cloning and Long Terminal Repeat Sequences of Human Endogenous Retrovirus Genes Related to Types A and B Retrovirus Genes. J. Virol. 1986, 58, 937–944. [Google Scholar] [CrossRef] [PubMed]
- Ono, M.; Yasunaga, T.; Miyata, T.; Ushikubo, H. Nucleotide Sequence of Human Endogenous Retrovirus Genome Related to the Mouse Mammary Tumor Virus Genome. J. Virol. 1986, 60, 589–598. [Google Scholar] [CrossRef] [PubMed]
- Xue, B.; Zeng, T.; Jia, L.; Yang, D.; Lin, S.L.; Sechi, L.A.; Kelvin, D.J. Identification of the Distribution of Human Endogenous Retroviruses K (HML-2) by PCR-Based Target Enrichment Sequencing. Retrovirology 2020, 17, 10. [Google Scholar] [CrossRef] [PubMed]
- Holloway, J.R.; Williams, Z.H.; Freeman, M.M.; Bulow, U.; Coffin, J.M. Gorillas Have Been Infected with the HERV-K (HML-2) Endogenous Retrovirus Much More Recently than Humans and Chimpanzees. Proc. Natl. Acad. Sci. USA 2019, 116, 1337–1346. [Google Scholar] [CrossRef] [PubMed]
- Bittner, J.J. Some Possible Effects of Nursing on the Mammary Gland Tumor Incidence in Mice. Science 1936, 84, 162. [Google Scholar] [CrossRef]
- Patience, C. Our Retroviral Heritage. Trends Genet. 1997, 13, 116–120. [Google Scholar] [CrossRef]
- Ting, C.N.; Rosenberg, M.P.; Snow, C.M.; Samuelson, L.C.; Meisler, M.H. Endogenous Retroviral Sequences are Required for Tissue-Specific Expression of a Human Salivary Amylase Gene. Genes Dev. 1992, 6, 1457–1465. [Google Scholar] [CrossRef]
- Cachon-Gonzalez, M.B.; Fenner, S.; Coffin, J.M.; Moran, C.; Best, S.; Stoye, J.P. Structure and Expression of the Hairless Gene of Mice. Proc. Natl. Acad. Sci. USA 1994, 91, 7717–7721. [Google Scholar] [CrossRef]
- Barbulescu, M.; Turner, G.; Seaman, M.I.; Deinard, A.S.; Kidd, K.K.; Lenz, J. Many Human Endogenous Retrovirus K (HERV-K) Proviruses are Unique to Humans. Curr. Biol. 1999, 9, PS1. [Google Scholar] [CrossRef] [PubMed]
- Golovkina, T.V.; Chervonsky, A.; Dudley, J.P.; Ross, S.R. Transgenic Mouse Mammary Tumor Virus Superantigen Expression Prevents Viral Infection. Cell 1992, 69, 637–645. [Google Scholar] [CrossRef] [PubMed]
- Ikeda, H.; Sugimura, H. Fv-4 Resistance Gene: A Truncated Endogenous Murine Leukemia Virus with Ecotropic Interference Properties. J. Virol. 1989, 63, 5405–5412. [Google Scholar] [CrossRef]
- Best, S.; Le Tissier, P.; Towers, G.; Stoye, J.P. Positional Cloning of the Mouse Retrovirus Restriction Gene Fvl. Nature 1996, 382, 826–829. [Google Scholar] [CrossRef] [PubMed]
- Grandi, N.; Tramontano, E. Human Endogenous Retroviruses are Ancient Acquired Elements Still Shaping Innate Immune Responses. Front. Immunol. 2018, 9, 2039. [Google Scholar] [CrossRef] [PubMed]
- Nelson, P.N.; Carnegie, P.R.; Martin, J.; Ejtehadi, H.D.; Hooley, P.; Roden, D.; Rowland-Jones, S.; Warren, P.; Astley, J.; Murray, P.G. Demystified… Human endogenous retroviruses. Mol. Pathol. 2003, 56, 11–18. [Google Scholar] [CrossRef] [PubMed]
- Montesion, M.; Bhardwaj, N.; Williams, Z.H.; Kuperwasser, C.; Coffin, J.M. Mechanisms of HERV-K (HML-2) Transcription during Human Mammary Epithelial Cell Transformation. J. Virol. 2018, 92, e01258-17. [Google Scholar] [CrossRef]
- Hughes, J.F.; Coffin, J.M. Human Endogenous Retrovirus K Solo-LTR Formation and Insertional Polymorphisms: Implications for Human and Viral Evolution. Proc. Natl. Acad. Sci. USA 2004, 101, 1668–1672. [Google Scholar] [CrossRef]
- Chen, J.; Foroozesh, M.; Qin, Z. Transactivation of Human Endogenous Retroviruses by Tumor Viruses and Their Functions in Virus-Associated Malignancies. Oncogenesis 2019, 8, 6. [Google Scholar] [CrossRef]
- Gifford, R.J.; Blomberg, J.; Coffin, J.M.; Fan, H.; Heidmann, T.; Mayer, J.; Stoye, J.; Tristem, M.; Johnson, W.E. Nomenclature for Endogenous Retrovirus (ERV) Loci. Retrovirology 2018, 15, 59. [Google Scholar] [CrossRef]
- KANKI, P.J.; HOPPER, J.R.; ESSEX, M. The Origins of HIV-1 and HTLV-4/HIV-2. Ann. NY Acad. Sci. 1987, 511, 370–375. [Google Scholar] [CrossRef]
- Göke, J.; Lu, X.; Chan, Y.-S.; Ng, H.-H.; Ly, L.-H.; Sachs, F.; Szczerbinska, I. Dynamic Transcription of Distinct Classes of Endogenous Retroviral Elements Marks Specific Populations of Early Human Embryonic Cells. Cell Stem. Cell 2015, 16, 135–141. [Google Scholar] [CrossRef] [PubMed]
- Alcazer, V.; Bonaventura, P.; Tonon, L.; Michel, E.; Mutez, V.; Fabres, C.; Chuvin, N.; Boulos, R.; Estornes, Y.; Maguer-Satta, V.; et al. HERVs Characterize Normal and Leukemia Stem Cells and Represent a Source of Shared Epitopes for Cancer Immunotherapy. Am. J. Hematol. 2022, 97, 1200–1214. [Google Scholar] [CrossRef] [PubMed]
- Grow, E.J.; Flynn, R.A.; Chavez, S.L.; Bayless, N.L.; Wossidlo, M.; Wesche, D.J.; Martin, L.; Ware, C.B.; Blish, C.A.; Chang, H.Y.; et al. Intrinsic Retroviral Reactivation in Human Preimplantation Embryos and Pluripotent Cells. Nature 2015, 522, 221–225. [Google Scholar] [CrossRef] [PubMed]
- Ruprecht, K.; Ferreira, H.; Flockerzi, A.; Wahl, S.; Sauter, M.; Mayer, J.; Mueller-Lantzsch, N. Human Endogenous Retrovirus Family HERV-K(HML-2) RNA Transcripts are Selectively Packaged into Retroviral Particles Produced by the Human Germ Cell Tumor Line Tera-1 and Originate Mainly from a Provirus on Chromosome 22q11.21. J. Virol. 2008, 82, 10008–10016. [Google Scholar] [CrossRef] [PubMed]
- Fuchs, N.V.; Loewer, S.; Daley, G.Q.; Izsvák, Z.; Löwer, J.; Löwer, R. Human Endogenous Retrovirus K (HML-2) RNA and Protein Expression Is a Marker for Human Embryonic and Induced Pluripotent Stem Cells. Retrovirology 2013, 10, 115. [Google Scholar] [CrossRef] [PubMed]
- Mao, J.; Zhang, Q.; Cong, Y.-S. Human Endogenous Retroviruses in Development and Disease. Comput. Struct. Biotechnol. J. 2021, 19, 5978–5986. [Google Scholar] [CrossRef] [PubMed]
- Wang, T.; Medynets, M.; Johnson, K.R.; Doucet-O’Hare, T.T.; DiSanza, B.; Li, W.; Xu, Y.; Bagnell, A.; Tyagi, R.; Sampson, K.; et al. Regulation of Stem Cell Function and Neuronal Differentiation by HERV-K via MTOR Pathway. Proc. Natl. Acad. Sci. USA 2020, 117, 17842–17853. [Google Scholar] [CrossRef]
- Bošković, A.; Eid, A.; Pontabry, J.; Ishiuchi, T.; Spiegelhalter, C.; Raghu Ram, E.V.S.; Meshorer, E.; Torres-Padilla, M.-E. Higher Chromatin Mobility Supports Totipotency and Precedes Pluripotency in Vivo. Genes Dev. 2014, 28, 1042–1047. [Google Scholar] [CrossRef]
- Fu, B.; Ma, H.; Liu, D. Endogenous Retroviruses Function as Gene Expression Regulatory Elements During Mammalian Pre-Implantation Embryo Development. Int. J. Mol. Sci. 2019, 20, 790. [Google Scholar] [CrossRef]
- Fu, B.; Ma, H.; Liu, D. Functions and Regulation of Endogenous Retrovirus Elements during Zygotic Genome Activation: Implications for Improving Somatic Cell Nuclear Transfer Efficiency. Biomolecules 2021, 11, 829. [Google Scholar] [CrossRef] [PubMed]
- Wang, J.; Xie, G.; Singh, M.; Ghanbarian, A.T.; Raskó, T.; Szvetnik, A.; Cai, H.; Besser, D.; Prigione, A.; Fuchs, N.V.; et al. Primate-Specific Endogenous Retrovirus-Driven Transcription Defines Naive-like Stem Cells. Nature 2014, 516, 405–409. [Google Scholar] [CrossRef] [PubMed]
- Manghera, M.; Ferguson-Parry, J.; Lin, R.; Douville, R.N. NF-ΚB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat. J. Virol. 2016, 90, 9338–9349. [Google Scholar] [CrossRef] [PubMed]
- Roulois, D.; Loo Yau, H.; Singhania, R.; Wang, Y.; Danesh, A.; Shen, S.Y.; Han, H.; Liang, G.; Jones, P.A.; Pugh, T.J.; et al. DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts. Cell 2015, 162, 961–973. [Google Scholar] [CrossRef] [PubMed]
- Chiappinelli, K.B.; Strissel, P.L.; Desrichard, A.; Li, H.; Henke, C.; Akman, B.; Hein, A.; Rote, N.S.; Cope, L.M.; Snyder, A.; et al. Inhibiting DNA Methylation Causes an Interferon Response in Cancer via DsRNA Including Endogenous Retroviruses. Cell 2015, 162, 974–986. [Google Scholar] [CrossRef] [PubMed]
- Soto, J.A.; Gálvez, N.M.S.; Andrade, C.A.; Pacheco, G.A.; Bohmwald, K.; Berrios, R.V.; Bueno, S.M.; Kalergis, A.M. The Role of Dendritic Cells During Infections Caused by Highly Prevalent Viruses. Front. Immunol. 2020, 11, 1513. [Google Scholar] [CrossRef] [PubMed]
- Nooraei, S.; Bahrulolum, H.; Hoseini, Z.S.; Katalani, C.; Hajizade, A.; Easton, A.J.; Ahmadian, G. Virus-like Particles: Preparation, Immunogenicity and Their Roles as Nanovaccines and Drug Nanocarriers. J. Nanobiotechnol. 2021, 19, 59. [Google Scholar] [CrossRef]
- Vergara Bermejo, A.; Ragonnaud, E.; Daradoumis, J.; Holst, P. Cancer Associated Endogenous Retroviruses: Ideal Immune Targets for Adenovirus-Based Immunotherapy. Int. J. Mol. Sci. 2020, 21, 4843. [Google Scholar] [CrossRef]
- Xue, B.; Sechi, L.A.; Kelvin, D.J. Human Endogenous Retrovirus K (HML-2) in Health and Disease. Front. Microbiol. 2020, 11, 1690. [Google Scholar] [CrossRef]
- Takahashi, K.; Nakamura, M.; Okubo, C.; Kliesmete, Z.; Ohnuki, M.; Narita, M.; Watanabe, A.; Ueda, M.; Takashima, Y.; Hellmann, I.; et al. The Pluripotent Stem Cell-Specific Transcript ESRG Is Dispensable for Human Pluripotency. PLoS Genet. 2021, 17, e1009587. [Google Scholar] [CrossRef]
- Greenig, M. HERVs, immunity, and autoimmunity: Understanding the connection. PeerJ 2019, 7, e6711. [Google Scholar] [CrossRef] [PubMed]
- Löwer, R.; Löwer, J.; Tondera-Koch, C.; Kurth, R. A General Method for the Identification of Transcribed Retrovirus Sequences (R-U5 PCR) Reveals the Expression of the Human Endogenous Retrovirus Loci HERV-H and HERV-K in Teratocarcinoma Cells. Virology 1993, 192, 501–511. [Google Scholar] [CrossRef] [PubMed]
- Garcia-Montojo, M.; Doucet-O’Hare, T.; Henderson, L.; Nath, A. Human Endogenous Retrovirus-K (HML-2): A Comprehensive Review. Crit. Rev. Microbiol. 2018, 44, 715–738. [Google Scholar] [CrossRef] [PubMed]
- Belshaw, R.; Dawson, A.L.A.; Woolven-Allen, J.; Redding, J.; Burt, A.; Tristem, M. Genomewide Screening Reveals High Levels of Insertional Polymorphism in the Human Endogenous Retrovirus Family HERV-K(HML2): Implications for Present-Day Activity. J. Virol. 2005, 79, 12507–12514. [Google Scholar] [CrossRef] [PubMed]
- Berkhout, B.; Jebbink, M.; Zsíros, J. Identification of an Active Reverse Transcriptase Enzyme Encoded by a Human Endogenous HERV-K Retrovirus. J. Virol. 1999, 73, 2365–2375. [Google Scholar] [CrossRef] [PubMed]
- Contreras-Galindo, R.; González, M.; Almodovar-Camacho, S.; González-Ramírez, S.; Lorenzo, E.; Yamamura, Y. A New Real-Time-RT-PCR for Quantitation of Human Endogenous Retroviruses Type K (HERV-K) RNA Load in Plasma Samples: Increased HERV-K RNA Titers in HIV-1 Patients with HAART Non-Suppressive Regimens. J. Virol. Methods 2006, 136, 51–57. [Google Scholar] [CrossRef] [PubMed]
- Amarante-Mendes, G.P.; Adjemian, S.; Branco, L.M.; Zanetti, L.C.; Weinlich, R.; Bortoluci, K.R. Pattern Recognition Receptors and the Host Cell Death Molecular Machinery. Front. Immunol. 2018, 9, 2379. [Google Scholar] [CrossRef]
- Abdul-Cader, M.S.; Amarasinghe, A.; Abdul-Careem, M.F. Activation of Toll-like Receptor Signaling Pathways Leading to Nitric Oxide-Mediated Antiviral Responses. Arch. Virol. 2016, 161, 2075–2086. [Google Scholar] [CrossRef]
- Rehwinkel, J.; Gack, M.U. RIG-I-like Receptors: Their Regulation and Roles in RNA Sensing. Nat. Rev. Immunol. 2020, 20, 537–551. [Google Scholar] [CrossRef]
- Jiang, Y.; Zhang, H.; Wang, J.; Chen, J.; Guo, Z.; Liu, Y.; Hua, H. Exploiting RIG-I-like Receptor Pathway for Cancer Immunotherapy. J. Hematol. Oncol. 2023, 16, 8. [Google Scholar] [CrossRef] [PubMed]
- Cipriani, C.; Tartaglione, A.M.; Giudice, M.; D’Avorio, E.; Petrone, V.; Toschi, N.; Chiarotti, F.; Miele, M.T.; Calamandrei, G.; Garaci, E.; et al. Differential Expression of Endogenous Retroviruses and Inflammatory Mediators in Female and Male Offspring in a Mouse Model of Maternal Immune Activation. Int. J. Mol. Sci. 2022, 23, 13930. [Google Scholar] [CrossRef] [PubMed]
- Dupressoir, A.; Lavialle, C.; Heidmann, T. From Ancestral Infectious Retroviruses to Bona Fide Cellular Genes: Role of the Captured Syncytins in Placentation. Placenta 2012, 33, 663–671. [Google Scholar] [CrossRef] [PubMed]
- Alcazer, V.; Bonaventura, P.; Depil, S. Human Endogenous Retroviruses (HERVs): Shaping the Innate Immune Response in Cancers. Cancers 2020, 12, 610. [Google Scholar] [CrossRef] [PubMed]
- Stauffer, Y.; Marguerat, S.; Meylan, F.; Ucla, C.; Sutkowski, N.; Huber, B.; Pelet, T.; Conrad, B. Interferon-α-Induced Endogenous Superantigen. Immunity 2001, 15, 591–601. [Google Scholar] [CrossRef] [PubMed]
- Tatkiewicz, W.; Dickie, J.; Bedford, F.; Jones, A.; Atkin, M.; Kiernan, M.; Maze, E.A.; Agit, B.; Farnham, G.; Kanapin, A.; et al. Characterising a Human Endogenous Retrovirus(HERV)-Derived Tumour-Associated Antigen: Enriched RNA-Seq Analysis of HERV-K(HML-2) in Mantle Cell Lymphoma Cell Lines. Mob. DNA 2020, 11, 9. [Google Scholar] [CrossRef] [PubMed]
- Rangel, S.C.; da Silva, M.D.; da Silva, A.L.; dos Santos, J.D.M.B.; Neves, L.M.; Pedrosa, A.; Rodrigues, F.M.; dos Santos Trettel, C.; Furtado, G.E.; de Barros, M.P.; et al. Human Endogenous Retroviruses and the Inflammatory Response: A Vicious Circle Associated with Health and Illness. Front. Immunol. 2022, 13, 1057791. [Google Scholar] [CrossRef]
- Burn, A.; Roy, F.; Freeman, M.; Coffin, J.M. Widespread Expression of the Ancient HERV-K (HML-2) Provirus Group in Normal Human Tissues. PLoS Biol. 2022, 20, e3001826. [Google Scholar] [CrossRef]
- Contreras-Galindo, R.; Kaplan, M.H.; Dube, D.; Gonzalez-Hernandez, M.J.; Chan, S.; Meng, F.; Dai, M.; Omenn, G.S.; Gitlin, S.D.; Markovitz, D.M. Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences. J. Virol. 2015, 89, 7187–7201. [Google Scholar] [CrossRef]
- Cuevas, M.V.R.; Hardy, M.-P.; Larouche, J.-D.; Apavaloaei, A.; Kina, E.; Vincent, K.; Gendron, P.; Laverdure, J.-P.; Durette, C.; Thibault, P.; et al. BamQuery: A Proteogenomic Tool to Explore the Immunopeptidome and Prioritize Actionable Tumor Antigens. Genome Biol. 2023, 24, 188. [Google Scholar] [CrossRef]
- Gao, Y.; Yu, X.-F.; Chen, T. Human Endogenous Retroviruses in Cancer: Expression, Regulation and Function (Review). Oncol. Lett. 2020, 21, 121. [Google Scholar] [CrossRef] [PubMed]
- Gröger, V.; Emmer, A.; Staege, M.; Cynis, H. Endogenous Retroviruses in Nervous System Disorders. Pharmaceuticals 2021, 14, 70. [Google Scholar] [CrossRef] [PubMed]
- Russ, E.; Iordanskiy, S. Endogenous Retroviruses as Modulators of Innate Immunity. Pathogens 2023, 12, 162. [Google Scholar] [CrossRef] [PubMed]
- Noli Truant, S.; Redolfi, D.M.; Sarratea, M.B.; Malchiodi, E.L.; Fernández, M.M. Superantigens, a Paradox of the Immune Response. Toxins 2022, 14, 800. [Google Scholar] [CrossRef]
- Rojas, M.; Restrepo-Jiménez, P.; Monsalve, D.M.; Pacheco, Y.; Acosta-Ampudia, Y.; Ramírez-Santana, C.; Leung, P.S.C.; Ansari, A.A.; Gershwin, M.E.; Anaya, J.-M. Molecular Mimicry and Autoimmunity. J. Autoimmun. 2018, 95, 100–123. [Google Scholar] [CrossRef] [PubMed]
- Grandi, N.; Tramontano, E. HERV Envelope Proteins: Physiological Role and Pathogenic Potential in Cancer and Autoimmunity. Front. Microbiol. 2018, 9, 462. [Google Scholar] [CrossRef]
- Chan, S.M.; Sapir, T.; Park, S.-S.; Rual, J.-F.; Contreras-Galindo, R.; Reiner, O.; Markovitz, D.M. The HERV-K Accessory Protein Np9 Controls Viability and Migration of Teratocarcinoma Cells. PLoS ONE 2019, 14, e0212970. [Google Scholar] [CrossRef]
- Singh, M.; Cai, H.; Bunse, M.; Feschotte, C.; Izsvák, Z. Human Endogenous Retrovirus K Rec Forms a Regulatory Loop with MITF That Opposes the Progression of Melanoma to an Invasive Stage. Viruses 2020, 12, 1303. [Google Scholar] [CrossRef]
- Attig, J.; Pape, J.; Doglio, L.; Kazachenka, A.; Ottina, E.; Young, G.R.; Enfield, K.S.S.; Aramburu, I.V.; Ng, K.W.; Faulkner, N.; et al. Human Endogenous Retrovirus Onco-Exaptation Counters Cancer Cell Senescence through Calbindin. J. Clin. Investig. 2023, 133, e164397. [Google Scholar] [CrossRef]
- Montesion, M.; Williams, Z.H.; Subramanian, R.P.; Kuperwasser, C.; Coffin, J.M. Promoter Expression of HERV-K (HML-2) Provirus-Derived Sequences Is Related to LTR Sequence Variation and Polymorphic Transcription Factor Binding Sites. Retrovirology 2018, 15, 57. [Google Scholar] [CrossRef]
- Thompson, P.J.; Macfarlan, T.S.; Lorincz, M.C. Long Terminal Repeats: From Parasitic Elements to Building Blocks of the Transcriptional Regulatory Repertoire. Mol. Cell 2016, 62, 766–776. [Google Scholar] [CrossRef]
- Santoni, F.A.; Guerra, J.; Luban, J. HERV-H RNA Is Abundant in Human Embryonic Stem Cells and a Precise Marker for Pluripotency. Retrovirology 2012, 9, 111. [Google Scholar] [CrossRef] [PubMed]
- She, J.; Du, M.; Xu, Z.; Jin, Y.; Li, Y.; Zhang, D.; Tao, C.; Chen, J.; Wang, J.; Yang, E. The Landscape of HervRNAs Transcribed from Human Endogenous Retroviruses across Human Body Sites. Genome Biol. 2022, 23, 231. [Google Scholar] [CrossRef] [PubMed]
- Zhang, M.; Zheng, S.; Liang, J.Q. Transcriptional and Reverse Transcriptional Regulation of Host Genes by Human Endogenous Retroviruses in Cancers. Front. Microbiol. 2022, 13, 946296. [Google Scholar] [CrossRef] [PubMed]
- Gröger, V.; Cynis, H. Human Endogenous Retroviruses and Their Putative Role in the Development of Autoimmune Disorders Such as Multiple Sclerosis. Front. Microbiol. 2018, 9, 265. [Google Scholar] [CrossRef] [PubMed]
- de la Hera, B.; Urcelay, E. HERVs in Multiple Sclerosis—From Insertion to Therapy. In Advances in Molecular Retrovirology; InTech: London, UK, 2016. [Google Scholar]
- Wallace, A.D.; Wendt, G.A.; Barcellos, L.F.; de Smith, A.J.; Walsh, K.M.; Metayer, C.; Costello, J.F.; Wiemels, J.L.; Francis, S.S. To ERV Is Human: A Phenotype-Wide Scan Linking Polymorphic Human Endogenous Retrovirus-K Insertions to Complex Phenotypes. Front. Genet. 2018, 9, 298. [Google Scholar] [CrossRef] [PubMed]
- Contreras-Galindo, R.; Kaplan, M.H.; Contreras-Galindo, A.C.; Gonzalez-Hernandez, M.J.; Ferlenghi, I.; Giusti, F.; Lorenzo, E.; Gitlin, S.D.; Dosik, M.H.; Yamamura, Y.; et al. Characterization of Human Endogenous Retroviral Elements in the Blood of HIV-1-Infected Individuals. J. Virol. 2012, 86, 262–276. [Google Scholar] [CrossRef]
- Srinivasachar Badarinarayan, S.; Shcherbakova, I.; Langer, S.; Koepke, L.; Preising, A.; Hotter, D.; Kirchhoff, F.; Sparrer, K.M.J.; Schotta, G.; Sauter, D. HIV-1 Infection Activates Endogenous Retroviral Promoters Regulating Antiviral Gene Expression. Nucleic Acids Res. 2020, 48, 10890–10908. [Google Scholar] [CrossRef]
- Rautonen, N.; Rautonen, J.; Martin, N.L.; Wara, D.W. HIV-1 Tat Induces Cytokine Synthesis by Uninfected Mononuclear Cells. AIDS 1994, 8, 1504–1505. [Google Scholar] [CrossRef]
- Li, X.; Guo, Y.; Li, H.; Huang, X.; Pei, Z.; Wang, X.; Liu, Y.; Jia, L.; Li, T.; Bao, Z.; et al. Infection by Diverse HIV-1 Subtypes Leads to Different Elevations in HERV-K Transcriptional Levels in Human T Cell Lines. Front. Microbiol. 2021, 12, 662573. [Google Scholar] [CrossRef]
- Young, G.R.; Terry, S.N.; Manganaro, L.; Cuesta-Dominguez, A.; Deikus, G.; Bernal-Rubio, D.; Campisi, L.; Fernandez-Sesma, A.; Sebra, R.; Simon, V.; et al. HIV-1 Infection of Primary CD4+ T Cells Regulates the Expression of Specific Human Endogenous Retrovirus HERV-K (HML-2) Elements. J. Virol. 2018, 92, e01507-17. [Google Scholar] [CrossRef] [PubMed]
- Braun, E.; Hotter, D.; Koepke, L.; Zech, F.; Groß, R.; Sparrer, K.M.J.; Müller, J.A.; Pfaller, C.K.; Heusinger, E.; Wombacher, R.; et al. Guanylate-Binding Proteins 2 and 5 Exert Broad Antiviral Activity by Inhibiting Furin-Characterization of Human Endogenous Retroviral Elements in the Blood of HIV-1-Infected IndividualsMediated Processing of Viral Envelope Proteins. Cell Rep. 2019, 27, 2092–2104.e10. [Google Scholar] [CrossRef] [PubMed]
- Wang, D.; Gomes, M.T.; Mo, Y.; Prohaska, C.C.; Zhang, L.; Chelvanambi, S.; Clauss, M.A.; Zhang, D.; Machado, R.F.; Gao, M.; et al. Human Endogenous Retrovirus, SARS-CoV-2, and HIV Promote PAH via Inflammation and Growth Stimulation. Int. J. Mol. Sci. 2023, 24, 7472. [Google Scholar] [CrossRef] [PubMed]
- Gonzalez-Hernandez, M.J.; Swanson, M.D.; Contreras-Galindo, R.; Cookinham, S.; King, S.R.; Noel, R.J.; Kaplan, M.H.; Markovitz, D.M. Expression of Human Endogenous Retrovirus Type K (HML-2) Is Activated by the Tat Protein of HIV-1. J. Virol. 2012, 86, 7790–7805. [Google Scholar] [CrossRef] [PubMed]
- Guo, Y.; Yang, C.; Liu, Y.; Li, T.; Li, H.; Han, J.; Jia, L.; Wang, X.; Zhang, B.; Li, J.; et al. High Expression of HERV-K (HML-2) Might Stimulate Interferon in COVID-19 Patients. Viruses 2022, 14, 996. [Google Scholar] [CrossRef] [PubMed]
- Temerozo, J.R.; Fintelman-Rodrigues, N.; dos Santos, M.C.; Hottz, E.D.; Sacramento, C.Q.; de Paula Dias da Silva, A.; Mandacaru, S.C.; dos Santos Moraes, E.C.; Trugilho, M.R.O.; Gesto, J.S.M.; et al. Human Endogenous Retrovirus K in the Respiratory Tract Is Associated with COVID-19 Physiopathology. Microbiome 2022, 10, 65. [Google Scholar] [CrossRef] [PubMed]
- Grandi, N.; Erbì, M.C.; Scognamiglio, S.; Tramontano, E. Human Endogenous Retrovirus (HERV) Transcriptome Is Dynamically Modulated during SARS-CoV-2 Infection and Allows Discrimination of COVID-19 Clinical Stages. Microbiol. Spectr. 2023, 11, e0251622. [Google Scholar] [CrossRef]
- Nyborg, J.K.; Egan, D.; Sharma, N. The HTLV-1 Tax Protein: Revealing Mechanisms of Transcriptional Activation through Histone Acetylation and Nucleosome Disassembly. Biochim. Biophys. Acta (BBA)-Gene Regul. Mech. 2010, 1799, 266–274. [Google Scholar] [CrossRef]
- Jones, R.B.; Leal, F.E.; Hasenkrug, A.M.; Segurado, A.C.; Nixon, D.F.; Ostrowski, M.A.; Kallas, E.G. Human Endogenous Retrovirus K(HML-2) Gag and Env Specific T-Cell Responses are Not Detected in HTLV-I-Infected Subjects Using Standard Peptide Screening Methods. J. Negat. Results Biomed. 2013, 12, 3. [Google Scholar] [CrossRef]
- Weber, M.; Padmanabhan Nair, V.; Bauer, T.; Sprinzl, M.F.; Protzer, U.; Vincendeau, M. Increased HERV-K(HML-2) Transcript Levels Correlate with Clinical Parameters of Liver Damage in Hepatitis C Patients. Cells 2021, 10, 774. [Google Scholar] [CrossRef]
- Wieland, L.; Schwarz, T.; Engel, K.; Volkmer, I.; Krüger, A.; Tarabuko, A.; Junghans, J.; Kornhuber, M.E.; Hoffmann, F.; Staege, M.S.; et al. Epstein-Barr Virus-Induced Genes and Endogenous Retroviruses in Immortalized B Cells from Patients with Multiple Sclerosis. Cells 2022, 11, 3619. [Google Scholar] [CrossRef] [PubMed]
- Graff, S.; Moore, D.H.; Stanley, W.M.; Randall, H.T.; Haagensen, C.D. Isolation of Mouse Mammary Carcinoma Virus. Cancer 1949, 2, 755–762. [Google Scholar] [CrossRef] [PubMed]
- Kaplan, M.H.; Contreras-Galindo, R.; Jiagge, E.; Merajver, S.D.; Newman, L.; Bigman, G.; Dosik, M.H.; Palapattu, G.S.; Siddiqui, J.; Chinnaiyan, A.M.; et al. Is the HERV-K HML-2 Xq21.33, an Endogenous Retrovirus Mutated by Gene Conversion of Chromosome X in a Subset of African Populations, Associated with Human Breast Cancer? Infect. Agent Cancer 2020, 15, 19. [Google Scholar] [CrossRef] [PubMed]
- Johanning, G.L.; Malouf, G.G.; Zheng, X.; Esteva, F.J.; Weinstein, J.N.; Wang-Johanning, F.; Su, X. Expression of Human Endogenous Retrovirus-K Is Strongly Associated with the Basal-like Breast Cancer Phenotype. Sci. Rep. 2017, 7, 41960. [Google Scholar] [CrossRef] [PubMed]
- Bonaventura, P.; Alcazer, V.; Mutez, V.; Tonon, L.; Martin, J.; Chuvin, N.; Michel, E.; Boulos, R.E.; Estornes, Y.; Valladeau-Guilemond, J.; et al. Identification of Shared Tumor Epitopes from Endogenous Retroviruses Inducing High-Avidity Cytotoxic T Cells for Cancer Immunotherapy. Sci. Adv. 2022, 8, eabj3671. [Google Scholar] [CrossRef] [PubMed]
- Goering, W.; Schmitt, K.; Dostert, M.; Schaal, H.; Deenen, R.; Mayer, J.; Schulz, W.A. Human Endogenous Retrovirus HERV-K(HML-2) Activity in Prostate Cancer Is Dominated by a Few Loci. Prostate 2015, 75, 1958–1971. [Google Scholar] [CrossRef] [PubMed]
- Büscher, K.; Trefzer, U.; Hofmann, M.; Sterry, W.; Kurth, R.; Denner, J. Expression of Human Endogenous Retrovirus K in Melanomas and Melanoma Cell Lines. Cancer Res. 2005, 65, 4172–4180. [Google Scholar] [CrossRef]
- Yang, C.; Guo, X.; Li, J.; Han, J.; Jia, L.; Wen, H.-L.; Sun, C.; Wang, X.; Zhang, B.; Li, J.; et al. Significant Upregulation of HERV-K (HML-2) Transcription Levels in Human Lung Cancer and Cancer Cells. Front. Microbiol. 2022, 13, 850444. [Google Scholar] [CrossRef]
- Kitsou, K.; Lagiou, P.; Magiorkinis, G. Human Endogenous Retroviruses in Cancer: Oncogenesis Mechanisms and Clinical Implications. J. Med. Virol. 2023, 95, 28350. [Google Scholar] [CrossRef]
- Bhardwaj, N.; Montesion, M.; Roy, F.; Coffin, J. Differential Expression of HERV-K (HML-2) Proviruses in Cells and Virions of the Teratocarcinoma Cell Line Tera-1. Viruses 2015, 7, 939–968. [Google Scholar] [CrossRef]
- Alarcón-Zendejas, A.P.; Scavuzzo, A.; Jiménez-Ríos, M.A.; Álvarez-Gómez, R.M.; Montiel-Manríquez, R.; Castro-Hernández, C.; Jiménez-Dávila, M.A.; Pérez-Montiel, D.; González-Barrios, R.; Jiménez-Trejo, F.; et al. The Promising Role of New Molecular Biomarkers in Prostate Cancer: From Coding and Non-Coding Genes to Artificial Intelligence Approaches. Prostate Cancer Prostatic Dis. 2022, 25, 431–443. [Google Scholar] [CrossRef] [PubMed]
- Wang-Johanning, F.; Li, M.; Esteva, F.J.; Hess, K.R.; Yin, B.; Rycaj, K.; Plummer, J.B.; Garza, J.G.; Ambs, S.; Johanning, G.L. Human Endogenous Retrovirus Type K Antibodies and MRNA as Serum Biomarkers of Early-Stage Breast Cancer. Int. J. Cancer 2014, 134, 587–595. [Google Scholar] [CrossRef] [PubMed]
- Wallace, T.A.; Downey, R.F.; Seufert, C.J.; Schetter, A.; Dorsey, T.H.; Johnson, C.A.; Goldman, R.; Loffredo, C.A.; Yan, P.; Sullivan, F.J.; et al. Elevated HERV-K MRNA Expression in PBMC Is Associated with a Prostate Cancer Diagnosis Particularly in Older Men and Smokers. Carcinogenesis 2014, 35, 2074–2083. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Q.; Pan, J.; Cong, Y.; Mao, J. Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases. Int. J. Mol. Sci. 2022, 23, 10112. [Google Scholar] [CrossRef]
- Morozov, V.A.; Dao Thi, V.L.; Denner, J. The Transmembrane Protein of the Human Endogenous Retrovirus—K (HERV-K) Modulates Cytokine Release and Gene Expression. PLoS ONE 2013, 8, e70399. [Google Scholar] [CrossRef]
- Dervan, E.; Bhattacharyya, D.D.; McAuliffe, J.D.; Khan, F.H.; Glynn, S.A. Ancient Adversary—HERV-K (HML-2) in Cancer. Front. Oncol. 2021, 11, 658489. [Google Scholar] [CrossRef]
- Argaw-Denboba, A.; Balestrieri, E.; Serafino, A.; Cipriani, C.; Bucci, I.; Sorrentino, R.; Sciamanna, I.; Gambacurta, A.; Sini-baldi-Vallebona, P.; Matteucci, C.; et al. HERV-K activation is strictly required to sustain CD133+ melanoma cells with stemness features. J. Exp. Clin. Cancer Res. 2017, 36, 1–17. [Google Scholar] [CrossRef]
- Chin, M.H.; Mason, M.J.; Xie, W.; Volinia, S.; Singer, M.; Peterson, C.; Ambartsumyan, G.; Aimiuwu, O.; Richter, L.; Zhang, J.; et al. Induced Pluripotent Stem Cells and Embryonic Stem Cells are Distinguished by Gene Expression Signatures. Cell Stem Cell 2009, 5, 111–123. [Google Scholar] [CrossRef]
- Schiavetti, F.; Thonnard, J.; Colau, D.; Boon, T.; Coulie, P.G. A Human Endogenous Retroviral Sequence Encoding an Antigen Recognized on Melanoma by Cytolytic T Lymphocytes. Cancer Res. 2002, 62, 5510–5516. [Google Scholar]
- Rezaei, S.D.; Hayward, J.A.; Norden, S.; Pedersen, J.; Mills, J.; Hearps, A.C.; Tachedjian, G. HERV-K Gag RNA and Protein Levels are Elevated in Malignant Regions of the Prostate in Males with Prostate Cancer. Viruses 2021, 13, 449. [Google Scholar] [CrossRef]
- Hosseiniporgham, S.; Sechi, L.A. Anti-HERV-K Drugs and Vaccines, Possible Therapies against Tumors. Vaccines 2023, 11, 751. [Google Scholar] [CrossRef]
- Contreras-Galindo, R.; Kaplan, M.H.; Leissner, P.; Verjat, T.; Ferlenghi, I.; Bagnoli, F.; Giusti, F.; Dosik, M.H.; Hayes, D.F.; Gitlin, S.D.; et al. Human Endogenous Retrovirus K (HML-2) Elements in the Plasma of People with Lymphoma and Breast Cancer. J. Virol. 2008, 82, 9329–9336. [Google Scholar] [CrossRef] [PubMed]
- Manca, M.A.; Solinas, T.; Simula, E.R.; Noli, M.; Ruberto, S.; Madonia, M.; Sechi, L.A. HERV-K and HERV-H Env Proteins Induce a Humoral Response in Prostate Cancer Patients. Pathogens 2022, 11, 95. [Google Scholar] [CrossRef]
- Mueller, T.; Hantsch, C.; Volkmer, I.; Staege, M.S. Differentiation-Dependent Regulation of Human Endogenous Retrovirus K Sequences and Neighboring Genes in Germ Cell Tumor Cells. Front. Microbiol. 2018, 9, 1253. [Google Scholar] [CrossRef] [PubMed]
- Galli, U.M.; Sauter, M.; Lecher, B.; Maurer, S.; Herbst, H.; Roemer, K.; Mueller-Lantzsch, N. Human endogenous retrovirus rec interferes with germ cell development in mice and may cause carcinoma in situ, the predecessor lesion of germ cell tumors. Oncogene 2005, 24, 3223–3228. [Google Scholar] [CrossRef]
- Li, M.; Radvanyi, L.; Yin, B.; Rycaj, K.; Li, J.; Chivukula, R.; Lin, K.; Lu, Y.; Shen, J.; Chang, D.Z.; et al. Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral Env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth. Clin. Cancer Res. 2017, 23, 5892–5911. [Google Scholar] [CrossRef] [PubMed]
- Ng, K.W.; Boumelha, J.; Enfield, K.S.S.; Almagro, J.; Cha, H.; Pich, O.; Karasaki, T.; Moore, D.A.; Salgado, R.; Sivakumar, M.; et al. Antibodies against Endogenous Retroviruses Promote Lung Cancer Immunotherapy. Nature 2023, 616, 563–573. [Google Scholar] [CrossRef]
- Hothi, P.; Cobbs, C. The Potential Role of Human Endogenous Retrovirus K in Glioblastoma. J. Clin. Investig. 2023, 133, e170885. [Google Scholar] [CrossRef]
- Cao, W.; Kang, R.; Xiang, Y.; Hong, J. Human Endogenous Retroviruses in Clear Cell Renal Cell Carcinoma: Biological Functions and Clinical Values. Onco Targets Ther. 2020, 13, 7877–7885. [Google Scholar] [CrossRef]
- Shah, A.H.; Rivas, S.R.; Doucet-O’Hare, T.T.; Govindarajan, V.; DeMarino, C.; Wang, T.; Ampie, L.; Zhang, Y.; Banasavadi-Siddegowda, Y.K.; Walbridge, S.; et al. Human Endogenous Retrovirus K Contributes to a Stem Cell Niche in Glioblastoma. J. Clin. Investig. 2023, 133, e167929. [Google Scholar] [CrossRef]
- Ko, E.-J.; Ock, M.-S.; Choi, Y.-H.; Iovanna, J.L.; Mun, S.; Han, K.; Kim, H.-S.; Cha, H.-J. Human Endogenous Retrovirus (HERV)-K Env Gene Knockout Affects Tumorigenic Characteristics of Nupr1 Gene in DLD-1 Colorectal Cancer Cells. Int. J. Mol. Sci. 2021, 22, 3941. [Google Scholar] [CrossRef]
- Ko, E.-J.; Kim, E.T.; Kim, H.; Lee, C.M.; Koh, S.B.; Eo, W.K.; Kim, H.; Oh, Y.L.; Ock, M.S.; Kim, K.H.; et al. Effect of Human Endogenous Retrovirus-K Env Gene Knockout on Proliferation of Ovarian Cancer Cells. Genes Genom. 2022, 44, 1091–1097. [Google Scholar] [CrossRef] [PubMed]
- Weyerer, V.; Strissel, P.L.; Stöhr, C.; Eckstein, M.; Wach, S.; Taubert, H.; Brandl, L.; Geppert, C.I.; Wullich, B.; Cynis, H.; et al. Endogenous Retroviral–K Envelope Is a Novel Tumor Antigen and Prognostic Indicator of Renal Cell Carcinoma. Front. Oncol. 2021, 11, 657187. [Google Scholar] [CrossRef] [PubMed]
- Dube, D.; Contreras-Galindo, R.; He, S.; King, S.R.; Gonzalez-Hernandez, M.J.; Gitlin, S.D.; Kaplan, M.H.; Markovitz, D.M. Genomic Flexibility of Human Endogenous Retrovirus Type K. J. Virol. 2014, 88, 9673–9682. [Google Scholar] [CrossRef] [PubMed]
- Rigogliuso, G.; Biniossek, M.L.; Goodier, J.L.; Mayer, B.; Pereira, G.C.; Schilling, O.; Meese, E.; Mayer, J. A Human Endogenous Retrovirus Encoded Protease Potentially Cleaves Numerous Cellular Proteins. Mob. DNA 2019, 10, 36. [Google Scholar] [CrossRef] [PubMed]
- Tyagi, R.; Li, W.; Parades, D.; Bianchet, M.A.; Nath, A. Inhibition of Human Endogenous Retrovirus-K by Antiretroviral Drugs. Retrovirology 2017, 14, 21. [Google Scholar] [CrossRef] [PubMed]
- Benoit, I.; Brownell, S.; Douville, R.N. Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme. Microorganisms 2021, 9, 1509. [Google Scholar] [CrossRef] [PubMed]
- Dewannieux, M.; Harper, F.; Richaud, A.; Letzelter, C.; Ribet, D.; Pierron, G.; Heidmann, T. Identification of an Infectious Progenitor for the Multiple-Copy HERV-K Human Endogenous Retroelements. Genome Res. 2006, 16, 1548–1556. [Google Scholar] [CrossRef]
- Beghi, E.; Chio, A.; Inghilleri, M.; Mazzini, L.; Micheli, A.; Mora, G.; Poloni, M.; Riva, R.; Serlenga, L.; Testa, D.; et al. A Randomized Controlled Trial of Recombinant Interferon Beta-1a in ALS. Neurology 2000, 54, 469. [Google Scholar] [CrossRef]
- Liu, C.-H.; Grandi, N.; Palanivelu, L.; Tramontano, E.; Lin, L.-T. Contribution of Human Retroviruses to Disease Development—A Focus on the HIV– and HERV–Cancer Relationships and Treatment Strategies. Viruses 2020, 12, 852. [Google Scholar] [CrossRef]
- Arru, G.; Galleri, G.; Deiana, G.A.; Zarbo, I.R.; Sechi, E.; Bo, M.; Cadoni, M.P.L.; Corda, D.G.; Frau, C.; Simula, E.R.; et al. HERV-K Modulates the Immune Response in ALS Patients. Microorganisms 2021, 9, 1784. [Google Scholar] [CrossRef]
- Tomasselli, A.G.; Heinrikson, R.L. [15] Specificity of Retroviral Proteases: An Analysis of Viral and Nonviral Protein Substrates. In Methods in Enzymology; Academic Press: Cambridge, MA, USA, 1994; pp. 279–301. [Google Scholar]
- Baldwin, E.T.; Götte, M.; Tchesnokov, E.P.; Arnold, E.; Hagel, M.; Nichols, C.; Dossang, P.; Lamers, M.; Wan, P.; Steinbacher, S.; et al. Human Endogenous Retrovirus-K (HERV-K) Reverse Transcriptase (RT) Structure and Biochemistry Reveals Remarkable Similarities to HIV-1 RT and Opportunities for HERV-K–Specific Inhibition. Proc. Natl. Acad. Sci. USA 2022, 119, e2200260119. [Google Scholar] [CrossRef] [PubMed]
- Wang-Johanning, F.; Rycaj, K.; Plummer, J.B.; Li, M.; Yin, B.; Frerich, K.; Garza, J.G.; Shen, J.; Lin, K.; Yan, P.; et al. Immunotherapeutic Potential of Anti-Human Endogenous Retrovirus-K Envelope Protein Antibodies in Targeting Breast Tumors. JNCI J. Natl. Cancer Inst. 2012, 104, 189–210. [Google Scholar] [CrossRef] [PubMed]
- Topper, M.J.; Vaz, M.; Marrone, K.A.; Brahmer, J.R.; Baylin, S.B. The Emerging Role of Epigenetic Therapeutics in Immuno-Oncology. Nat. Rev. Clin. Oncol. 2020, 17, 75–90. [Google Scholar] [CrossRef] [PubMed]
- Maze, E.A.; Agit, B.; Reeves, S.; Hilton, D.A.; Parkinson, D.B.; Laraba, L.; Ercolano, E.; Kurian, K.M.; Hanemann, C.O.; Belshaw, R.D.; et al. Human Endogenous Retrovirus Type K Promotes Proliferation and Confers Sensitivity to Antiretroviral Drugs in Merlin-Negative Schwannoma and Meningioma. Cancer Res. 2022, 82, 235–247. [Google Scholar] [CrossRef] [PubMed]
- Schmitt, K.; Reichrath, J.; Roesch, A.; Meese, E.; Mayer, J. Transcriptional Profiling of Human Endogenous Retrovirus Group HERV-K(HML-2) Loci in Melanoma. Genome Biol. Evol. 2013, 5, 307–328. [Google Scholar] [CrossRef] [PubMed]
- Kang, Q.; Guo, X.; Li, T.; Yang, C.; Han, J.; Jia, L.; Liu, Y.; Wang, X.; Zhang, B.; Li, J.; et al. Identification of Differentially Expressed HERV-K(HML-2) Loci in Colorectal Cancer. Front. Microbiol. 2023, 14, 1192900. [Google Scholar] [CrossRef] [PubMed]
- Yang, J.C.; Perry-Lalley, D. The Envelope Protein of an Endogenous Murine Retrovirus Is a Tumor-Associated T-Cell Antigen for Multiple Murine Tumors. J. Immunother. 2000, 23, 177–183. [Google Scholar] [CrossRef]
- Kershaw, M.H.; Hsu, C.; Mondesire, W.; Parker, L.L.; Wang, G.; Overwijk, W.W.; Lapointe, R.; Yang, J.C.; Wang, R.F.; Restifo, N.P.; et al. Immunization against Endogenous Retroviral Tumor-Associated Antigens. Cancer Res. 2001, 61, 7920–7924. [Google Scholar]
- Wong, K.K.; Hassan, R.; Yaacob, N.S. Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes. Front. Oncol. 2021, 11, 624742. [Google Scholar] [CrossRef]
- Jansz, N.; Faulkner, G.J. Endogenous Retroviruses in the Origins and Treatment of Cancer. Genome Biol. 2021, 22, 147. [Google Scholar] [CrossRef]
- Hu, C.; Liu, X.; Zeng, Y.; Liu, J.; Wu, F. DNA Methyltransferase Inhibitors Combination Therapy for the Treatment of Solid Tumor: Mechanism and Clinical Application. Clin. Epigenet. 2021, 13, 166. [Google Scholar] [CrossRef] [PubMed]
- Kordella, C.; Lamprianidou, E.; Kotsianidis, I. Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter. Front. Oncol. 2021, 11, 650473. [Google Scholar] [CrossRef] [PubMed]
- Alnefaie, A.; Albogami, S.; Asiri, Y.; Ahmad, T.; Alotaibi, S.S.; Al-Sanea, M.M.; Althobaiti, H. Chimeric Antigen Receptor T-Cells: An Overview of Concepts, Applications, Limitations, and Proposed Solutions. Front. Bioeng. Biotechnol. 2022, 10, 797440. [Google Scholar] [CrossRef] [PubMed]
- Akbari, B.; Ghahri-Saremi, N.; Soltantoyeh, T.; Hadjati, J.; Ghassemi, S.; Mirzaei, H.R. Epigenetic Strategies to Boost CAR T Cell Therapy. Mol. Ther. 2021, 29, 2640–2659. [Google Scholar] [CrossRef] [PubMed]
- Zhou, F.; Krishnamurthy, J.; Wei, Y.; Li, M.; Hunt, K.; Johanning, G.L.; Cooper, L.J.; Wang-Johanning, F. Chimeric Antigen Receptor T Cells Targeting HERV-K Inhibit Breast Cancer and Its Metastasis through Downregulation of Ras. Oncoimmunology 2015, 4, e1047582. [Google Scholar] [CrossRef]
- Krishnamurthy, J.; Rabinovich, B.A.; Mi, T.; Switzer, K.C.; Olivares, S.; Maiti, S.N.; Plummer, J.B.; Singh, H.; Kumaresan, P.R.; Huls, H.M.; et al. Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma. Clin. Cancer Res. 2015, 21, 3241–3251. [Google Scholar] [CrossRef] [PubMed]
- Rivas, S.R.; Valdez, M.J.M.; Govindarajan, V.; Seetharam, D.; Doucet-O’Hare, T.T.; Heiss, J.D.; Shah, A.H. The Role of HERV-K in Cancer Stemness. Viruses 2022, 14, 2019. [Google Scholar] [CrossRef]
- Chiale, C.; Marchese, A.M.; Furuya, Y.; Robek, M.D. Virus-Based Vaccine Vectors with Distinct Replication Mechanisms Differentially Infect and Activate Dendritic Cells. NPJ Vaccines 2021, 6, 138. [Google Scholar] [CrossRef]
- Daradoumis, J.; Ragonnaud, E.; Skandorff, I.; Nielsen, K.N.; Bermejo, A.V.; Andersson, A.-M.; Schroedel, S.; Thirion, C.; Neukirch, L.; Holst, P.J. An Endogenous Retrovirus Vaccine Encoding an Envelope with a Mutated Immunosuppressive Domain in Combination with Anti-PD1 Treatment Eradicates Established Tumours in Mice. Viruses 2023, 15, 926. [Google Scholar] [CrossRef]
- Abbott, R.; Hofland, T.; Hulen, T.; Verdegaal, E.E.; Crowther, M.; Dukes, J.; Khan, S.; de Kok, P.; Masi, G.; Met, Ö.; et al. 343 Identification of Tumor-Reactive T Cells Targeting Melanoma Dark AntigensTM Validates This Novel Class of Targets for Development of Immunotherapies. In Proceedings of the Regular and Young Investigator Award Abstracts; BMJ Publishing Group Ltd.: Boston, MA, USA, 2022; p. A361. [Google Scholar]
- Neukirch, L.; Nielsen, T.K.; Laursen, H.; Daradoumis, J.; Thirion, C.; Holst, P.J. Adenovirus Based Virus-like-Vaccines Targeting Endogenous Retroviruses Can Eliminate Growing Colorectal Cancers in Mice. Oncotarget 2019, 10, 1458–1472. [Google Scholar] [CrossRef]
- Kraus, B.; Fischer, K.; Büchner, S.M.; Wels, W.S.; Löwer, R.; Sliva, K.; Schnierle, B.S. Vaccination Directed against the Human Endogenous Retrovirus-K Envelope Protein Inhibits Tumor Growth in a Murine Model System. PLoS ONE 2013, 8, e72756. [Google Scholar] [CrossRef] [PubMed]
- Zhu, S.; Zhang, T.; Zheng, L.; Liu, H.; Song, W.; Liu, D.; Li, Z.; Pan, C. Combination Strategies to Maximize the Benefits of Cancer Immunotherapy. J. Hematol. Oncol. 2021, 14, 156. [Google Scholar] [CrossRef] [PubMed]
- Rasul, M.F.; Hussen, B.M.; Salihi, A.; Ismael, B.S.; Jalal, P.J.; Zanichelli, A.; Jamali, E.; Baniahmad, A.; Ghafouri-Fard, S.; Basiri, A.; et al. Strategies to Overcome the Main Challenges of the Use of CRISPR/Cas9 as a Replacement for Cancer Therapy. Mol. Cancer 2022, 21, 64. [Google Scholar] [CrossRef] [PubMed]
- Hussain, S.; Yalvac, M.E.; Khoo, B.; Eckardt, S.; McLaughlin, K.J. Adapting CRISPR/Cas9 System for Targeting Mitochondrial Genome. Front. Genet. 2021, 12, 627050. [Google Scholar] [CrossRef] [PubMed]
- Morozov, V.A.; Morozov, A.V. A Comprehensive Analysis of Human Endogenous Retroviruses HERV-K (HML.2) from Teratocarcinoma Cell Lines and Detection of Viral Cargo in Microvesicles. Int. J. Mol. Sci. 2021, 22, 12398. [Google Scholar] [CrossRef] [PubMed]
- Vitiello, G.A.F.; Ferreira, W.A.S.; Cordeiro de Lima, V.C.; da Silva Medina, T. Antiviral Responses in Cancer: Boosting Antitumor Immunity Through Activation of Interferon Pathway in the Tumor Microenvironment. Front. Immunol. 2021, 12, 782852. [Google Scholar] [CrossRef] [PubMed]
- Shih, W.-L.; Fang, C.-T.; Chen, P.-J. Anti-Viral Treatment and Cancer Control. In Viruses and Human Cancer; Springer: Berlin/Heidelberg, Germany, 2014; pp. 269–290. [Google Scholar]
- Liu, Y.; Zheng, C.; Huang, Y.; He, M.; Xu, W.W.; Li, B. Molecular Mechanisms of Chemo- and Radiotherapy Resistance and the Potential Implications for Cancer Treatment. MedComm 2021, 2, 315–340. [Google Scholar] [CrossRef]
- Giovinazzo, A.; Balestrieri, E.; Petrone, V.; Argaw-Denboba, A.; Cipriani, C.; Miele, M.T.; Grelli, S.; Sinibaldi-Vallebona, P.; Matteucci, C. The Concomitant Expression of Human Endogenous Retroviruses and Embryonic Genes in Cancer Cells under Microenvironmental Changes is a Potential Target for Antiretroviral Drugs. Cancer Microenviron. 2019, 12, 105–118. [Google Scholar] [CrossRef]
- Tatarova, Z.; Jonas, O.; Gray, J.W. Identifying Drug Combinations That Enhance Treatment Responses Mediated by the Tumor Microenvironment. Nat. Biotechnol. 2022, 40, 1770–1771. [Google Scholar] [CrossRef]
- Lower, R.; Lower, J.; Frank, H.; Harzmann, R.; Kurth, R. Human teratocarcinomas cultured in vitro produce unique retrovirus-like viruses. J. Gen. Virol. 1984, 65, 887–898. [Google Scholar] [CrossRef]
- Gotzinger, N.; Sauter, M.; Roemer, K.; Mueller-Lantzsch, N. Regulation of Human Endogenous Retrovirus-K Gag Expression in Teratocarcinoma Cell Lines and Human Tumours. J. Gen. Virol. 1996, 77, 2983–2990. [Google Scholar] [CrossRef]
- Tönjes, R.R.; Boller, K.; Limbach, C.; Lugert, R.; Kurth, R. Characterization of Human Endogenous Retrovirus Type K Virus-like Particles Generated from Recombinant Baculoviruses. Virology 1997, 233, 280–291. [Google Scholar] [CrossRef]
- Jonsson, E.N.; Karlsson, M.O. Automated Covariate Model Building within NONMEM. Pharm. Res. 1998, 15, 1463–1468. [Google Scholar] [CrossRef]
- Zechner, C.; Ruess, J.; Krenn, P.; Pelet, S.; Peter, M.; Lygeros, J.; Koeppl, H. Moment-Based Inference Predicts Bimodality in Transient Gene Expression. Proc. Natl. Acad. Sci. USA 2012, 109, 8340–8345. [Google Scholar] [CrossRef]
- Karlsson, M.; Janzén, D.L.I.; Durrieu, L.; Colman-Lerner, A.; Kjellsson, M.C.; Cedersund, G. Nonlinear Mixed-Effects Modelling for Single Cell Estimation: When, Why, and How to Use It. BMC Syst. Biol. 2015, 9, 52. [Google Scholar] [CrossRef]
- Bendall, M.L.; de Mulder, M.; Iñiguez, L.P.; Lecanda-Sánchez, A.; Pérez-Losada, M.; Ostrowski, M.A.; Jones, R.B.; Mulder, L.C.F.; Reyes-Terán, G.; Crandall, K.A.; et al. Telescope: Characterization of the Retrotranscriptome by Accurate Estimation of Transposable Element Expression. PLoS Comput. Biol. 2019, 15, e1006453. [Google Scholar] [CrossRef] [PubMed]
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). |
The Virus Implicated with HERV-K (HML-2) | Summary |
---|---|
HIV-1 | HIV-1 infection activates HERV-K (HML-2) loci, particularly LTR12C repeats associated with antiviral immunity. HERV-K (HML-2) upregulation associated with immune dysregulation, inflammation, and involvement in HIV pathogenesis. |
COVID-19 | High expression of HERV-K (HML-2) observed in COVID-19 patients, linked to interferon secretion. |
HTLV-1 | HTLV-1 infection induces the expression of HERV antigens, leading to the activation of HERV-specific T-cell responses. |
HCV-infected patients with liver cirrhosis | Increased levels of HERV-K (HML-2) transcripts in HCV-infected patients with liver cirrhosis, indicating a correlation between HERV expression and reduced liver function. |
EBV | Increased expression of HERV-K loci and other genes associated with relapses in MS. |
Class | Possible Mechanism of Action in HERV-K (HML-2) | Drug | References |
---|---|---|---|
Non-Nucleoside Reverse Transcriptase Inhibitor | HERV-K (HML-2) also encodes the reverse transcriptase enzyme, which is involved in the conversion of its RNA genome into DNA for integration into the human genome. Therefore, NNRTIs could inhibit the reverse transcription process of HERV-K (HML-2), leading to reduced viral DNA synthesis and integration. | Etravirine | [11] |
Nevirapine | [143] | ||
Cabovir | [144] | ||
Efavirenz | [143] | ||
Cabotegravir | NA | ||
Delavirdine | NA | ||
Doravirine | NA | ||
Rilpivirine | NA | ||
Abacavir | [138] | ||
Lamivudine | NA | ||
Zidovudine | [145] | ||
Didanosine | NA | ||
Emtricitabine | NA | ||
Stavudine | [143] | ||
Tenofovir disoproxil fumurate | NA | ||
Protease Inhibitors | HERV-K (HML-2) also encodes protease enzymes, and inhibiting this protease could interfere with the proper maturation of HERV-K (HML-2) viral particles. This could produce noninfectious HERV-K (HML-2) particles, reducing their ability to spread and infect new cells. | Ritonavir | NA |
Atazanavir | NA | ||
Darunavir | [146] | ||
Fosamprenavir | NA | ||
Indinavir | NA | ||
Lopinavir | [146] | ||
Nelfinavir | NA | ||
Ritonavir | NA | ||
Saquinavir | NA | ||
Tipranavir | NA | ||
Integrase Inhibitors | HERV-K (HML-2) relies on its integrase enzyme to integrate its DNA into the human genome. Integrase inhibitors could block this step, preventing the stable integration of HERV-K (HML-2) DNA into the host cell genome. This could lead to incomplete replication and reduced viral spread. | Elvitegravir | NA |
Dolutegravir | [138] | ||
Bictegravir | NA | ||
Cabotegravir | NA | ||
Raltegravir | [143] |
NCT Number | Title | Status | Condition | Intervention | Characteristics | Population |
---|---|---|---|---|---|---|
NCT02437110 | HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS) | Active, not Recruiting | Amyotrophic Lateral Sclerosis | Drug: Darunavir Ritonavir Dolutegravir Tenofovir alafenamide (TAF) | Study Type: Interventional Phase: Phase 1 Primary Purpose: Treatment | Enrollment: 122 Age: 18 Years and older (Adult, Older Adult) Sex: All |
NCT01528865 | Safety and Efficacy of Lamivudine and Tenofovir to Lower Plasma Level of Viral RNA in Lymphoma | Withdrawn | Lymphoma | Drug: Lamivudine Drug: Tenofovir disoproxil fumarate | Study Type: Interventional Phase: Phase 1 Phase 2 Primary Purpose: Viral load and tumor regression | Enrollment: 0 Age: 18 Years and older (Adult, Older Adult) Sex: All |
NCT02171884 | Study of the Impact of Freezing/Thawing Procedure and the Prolonged Culture of Embryos on Epigenetic Regulation in Humans | Recruiting | Assisted Reproductive Technology Freezing/Thawing Procedure and Prolonged Culture Procedure | Other: Sample of cord blood Other: Sample of placenta | Study Type: Observational Study Design: Observational Model: Cohort Time Perspective: Prospective Outcome | Enrollment: 366 Age: 18 Years to 50 Years (Adult) Sex: All |
NCT05193994 | Triumeq in Amyotrophic Lateral Sclerosis (LIGHTHOUSE II) | Recruiting | Amyotrophic Lateral Sclerosis | Drug: Dolutegravir, Abacavir and Lamivudine Drug: Placebo | Study Type: Interventional Phase: Phase 3 Study Design: Allocation: Randomized Intervention Primary Purpose: Treatment Outcome | Enrollment: 390 Age: 18 Years and older (Adult, Older Adult) Sex: Al |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Costa, B.; Vale, N. Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions. Int. J. Mol. Sci. 2023, 24, 14631. https://doi.org/10.3390/ijms241914631
Costa B, Vale N. Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions. International Journal of Molecular Sciences. 2023; 24(19):14631. https://doi.org/10.3390/ijms241914631
Chicago/Turabian StyleCosta, Bárbara, and Nuno Vale. 2023. "Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions" International Journal of Molecular Sciences 24, no. 19: 14631. https://doi.org/10.3390/ijms241914631