Role Of Human Endogenous Retroviruses Research Articles

EPCO-13. HUMAN ENDOGENOUS RETROVIRUS (HERV) PLAYS A CRITICAL ROLE IN ONCOGENIC MECHANISM INIDH1-WILD TYPE GLIOBLASTOMAS

Abstract IDH1-wildtype (WT) GBMs are the most common and aggressive tumors of the central nervous system (CNS), with a median survival rate of 12-15 months, and are resistant to clinical therapies due to their heterogenous molecular phenotype. In this study, we developed a pipeline to dissect the potential role of human endogenous retroviruses (HERVs) in patient derived glioma stem cells (GSCs) and integrated our findings with published epigenomic datasets for enhancers (H3K27ac), CTCF, and chromatin toplogy (Hi-C). We found high expression of several HERV transcripts in IDH1-WT GBMs as compared to IDH1-mutant variants. Epigenomic analysis of these upregulated HERVs showed association with both enhancer marks and CTCF deposition. Annotation of HERVs to their nearest genes, followed by Gene Set Enrichment Analysis (GSEA), identified involvement of actin-filament based mechanisms and regulation of immune phenotype. Integration of these findings identified MER61 (ERVMER61-1), a potential regulator of Interleukin-6 and showed alteration in chromatin looping and enhancer occupancy. To summarize, our work points to novel mechanisms of GBM pathogenesis, through involvement of HERVs in cell migratory and immune dysfunction, warranting further investigations into these oncogenic mechanism to identify and develop novel therapeutic options for GBM.

HERV-Derived Syncytin-1 and Syncytin-2 as Sources of Linear and Discontinuous Epitopes in Antiphospholipid Syndrome: A Pivotal Computational Study.

To date, no studies have investigated the potential reactivation of human endogenous retroviruses (HERVs) in the pathogenesis of antiphospholipid syndrome (APS). HERV-derived syncytin-1 and syncytin-2 are localized in the plasma membrane of cells and physiologically expressed during pregnancy. The current study aimed to determine whether the epitopes of syncytins can trigger an immune response leading to APS in genetically predisposed individuals. The TepiTool, ABCpred, and DiscoTope servers were utilized to predict T-cell and B-cell epitopes by inputting the FASTA sequences and 3D structures of syncytin-1, syncytin-2, and β2-glycoprotein I (β2GPI), which served as a reference antigen for APS. T-cell epitopes were selected based on their binding to a panel of human leukocyte antigen (HLA) class II alleles associated with APS according to the literature. Epitope predictions for the different proteins were statistically compared using GraphPad Prism. For syncytin-1, we identified a total of 721 T-cell epitopes, 51 linear B-cell epitopes, and up to 40 conformational epitopes. For syncytin-2, we predicted 705 T-cell epitopes and 28 linear B-cell epitopes, but a lower number of conformational epitopes, which also exhibited lower B-cell receptor (BCR)-binding scores. The predicted T-cell and B-cell conformational epitopes of both syncytin-1 and syncytin-2 demonstrated significantly higher binding affinity to selected HLA alleles and BCR compared with β2GPI. Furthermore, syncytin-1 exhibited significantly higher immunogenicity than syncytin-2. Both syncytin-1 and syncytin-2 are computationally endowed with potential epitopes that may activate either T cells or B cells in individuals genetically predisposed to APS. While these findings may illuminate the possible role of HERVs in the development of APS, they warrant validation in further laboratory studies.

Abstract 6432: Co-expression of HERV-R, CCND1, BRAF, FOXA1, TMPRSS2, ATF4 and low expression of BAZ1B and KMT2D is associated with early detection and poor prognosis of prostate cancer in African Black men from Nigeria

Abstract Prostate cancer (CaP) is a heterogeneous disease characterized by features of non-aggressive, slow-growing disorders to fast-growing disease. Men of African ancestry have disproportionately higher incidence and mortality rates for CaP than men of European ancestry. While there is evidence for a higher genetic predisposition for incidence of CaP in men of African ancestry compared to men of European ancestry, there is paucity of molecular biology and transcriptomic studies on the role of Human endogenous retroviruses (HERVs) in relation to CaP-associated genes in CaP pathogenesis and prognosis. In this study, we performed bulk RNA sequencing (RNA-seq) on formalin-fixed paraffin-embeded (FFPE) CaP samples from Nigerian CaP patients to investigate the expression significance of HERV-R in relation to FOXA1, TMPRSS2, BAZ1B, KMT2D, ATF4 and BRAF genes. Based on this findings, we used immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA) and immunofluorescence (IF) to confirm the expression pattern of the HERV-R and FOXA1, TMPRSS2, BAZ1B, KMT2D, ATF4 and BRAF proteins on 45 FFPE CaP and blood plasma samples, and 5 CaP-free samples from patients in Zaria, Nigeria. Most of these patients were longitudinally followed from 2017 to date. The DESeq2 procedure was used for data processing, analysis, and differential expression analysis of the aforementioned genes. We found a significant expression of HERV-R in relation with FOXA1, TMPRSS2, BAZ1B, KMT2D, ATF4, CCND1 and BRAF in the CaP from rural Africans in Nigeria. HERV-R expression was found to be associated with increased PSA level, higher Gleason grade and poor prognosis of CaP. A CaP sample from an 80-year-old patient that was histologically diagnosed to have no malignancy seen despite high PSA level of >100 and poor disease outcomes shows a significant cytoplasmic expression of HERV-R, indicating that HERV-R may serve as an important biomarker for early detection. Unfortunately, we lost the 80-year-old patient to late detection before revisiting his case for proper histological diagnosis and management. In addition, some histologically diagnosed BPH samples that are apparently reported to be CaP-free show stromal cells expression of HERV-R and in some cases show expression of HERV-R in the prostatic glandular areas. In contrast, stromal cells of the CaP samples show no expression of HERV-R, but strong expression in the glandular areas. This may implicate a gradual transition from benign prostatic lesion to malignant prostatic disease. HERV-R expression in CaP may have a relationship with BRAF, CCND1, FOXA1, TMPRSS2 and ATF4 genes. These findings combined together, underscore the importance of the expanded concept of HERV-R expression and CaP associated genes in early detection of CaP and prognosis. Citation Format: Faruk Mohammed, Konrad Stawiski, Halimatu Sadiya Musa, Sani Kamarudeen Owolabi, Sani Abubakar, Solomon O. Rotimi, Adoke Kasimu Umar, Yawale Iliyasu, Ahmad Bello, Folakemi T. Odedina, Clayton C. Yates, Kevin Petrie, Franklin W. Huang, Sani Ibrahim. Co-expression of HERV-R, CCND1, BRAF, FOXA1, TMPRSS2, ATF4 and low expression of BAZ1B and KMT2D is associated with early detection and poor prognosis of prostate cancer in African Black men from Nigeria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6432.

Roles of Human Endogenous Retroviruses and Endogenous Virus-Like Elements in Cancer Development and Innate Immunity.

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the host genome. Although mutations and silencing mechanisms impair their original role in viral replication, HERVs are believed to play roles in various biological processes. Long interspersed nuclear elements (LINEs) are non-LTR retrotransposons that have a lifecycle resembling that of retroviruses. Although LINE expression is typically silenced in somatic cells, it also contributes to various biological processes. The aberrant expression of HERVs and LINEs is closely associated with the development of cancer and/or immunological diseases, suggesting that they are integrated into various pathways related to the diseases. HERVs/LINEs control gene expression depending on the context as promoter/enhancer elements. Some RNAs and proteins derived from HERVs/LINEs have oncogenic potential, whereas others stimulate innate immunity. Non-retroviral endogenous viral elements (nrEVEs) are a novel type of virus-like element in the genome. nrEVEs may also be involved in host immunity. This article provides a current understanding of how these elements impact cellular physiology in cancer development and innate immunity, and provides perspectives for future studies.

Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions.

This review investigates the intricate role of human endogenous retroviruses (HERVs) in cancer development and progression, explicitly focusing on HERV-K (HML-2). This paper sheds light on the latest research advancements and potential treatment strategies by examining the historical context of HERVs and their involvement in critical biological processes such as embryonic development, immune response, and disease progression. This review covers computational modeling for drug-target binding assessment, systems biology modeling for simulating HERV-K viral cargo dynamics, and using antiviral drugs to combat HERV-induced diseases. The findings presented in this review contribute to our understanding of HERV-mediated disease mechanisms and provide insights into future therapeutic approaches. They emphasize why HERV-K holds significant promise as a biomarker and a target.

The potential role of human endogenous retrovirus K in glioblastoma.

The most active human endogenous retrovirus K (HERV-K) subtype, HML-2, has been implicated as a driver of oncogenesis in several cancers. However, the presence and function of HML-2 in malignant gliomas has remained unclear. In this issue of the JCI, Shah and colleagues demonstrate HML-2 overexpression in glioblastoma (GBM) and its role in maintaining the cancer stem cell phenotype. Given that stem-like cells are considered responsible for GBM heterogeneity and treatment resistance, targeting the stem cell niche may reduce tumor recurrence and improve clinical outcomes. The findings provide a foundation for future studies to determine whether antiretroviral and/or immunotherapy approaches targeting HML-2 could be used as therapeutics for GBM.

Pregnancy Is Associated with Impaired Transcription of Human Endogenous Retroviruses and of TRIM28 and SETDB1, Particularly in Mothers Affected by Multiple Sclerosis

Accumulating evidence highlights the pathogenetic role of human endogenous retroviruses (HERVs) in eliciting and maintaining multiple sclerosis (MS). Epigenetic mechanisms, such as those regulated by TRIM 28 and SETDB1, are implicated in HERV activation and in neuroinflammatory disorders, including MS. Pregnancy markedly improves the course of MS, but no study explored the expressions of HERVs and of TRIM28 and SETDB1 during gestation. Using a polymerase chain reaction real-time Taqman amplification assay, we assessed and compared the transcriptional levels of pol genes of HERV-H, HERV-K, HERV-W; of env genes of Syncytin (SYN)1, SYN2, and multiple sclerosis associated retrovirus (MSRV); and of TRIM28 and SETDB1 in peripheral blood and placenta from 20 mothers affected by MS; from 27 healthy mothers, in cord blood from their neonates; and in blood from healthy women of child-bearing age. The HERV mRNA levels were significantly lower in pregnant than in nonpregnant women. Expressions of all HERVs were downregulated in the chorion and in the decidua basalis of MS mothers compared to healthy mothers. The former also showed lower mRNA levels of HERV-K-pol and of SYN1, SYN2, and MSRV in peripheral blood. Significantly lower expressions of TRIM28 and SETDB1 also emerged in pregnant vs. nonpregnant women and in blood, chorion, and decidua of mothers with MS vs. healthy mothers. In contrast, HERV and TRIM28/SETDB1 expressions were comparable between their neonates. These results show that gestation is characterized by impaired expressions of HERVs and TRIM28/SETDB1, particularly in mothers with MS. Given the beneficial effects of pregnancy on MS and the wealth of data suggesting the putative contribution of HERVs and epigenetic processes in the pathogenesis of the disease, our findings may further support innovative therapeutic interventions to block HERV activation and to control aberrant epigenetic pathways in MS-affected patients.

Abstract P4-08-25: Unravelling the role of human endogenous retrovirus K (HERV-K) in inducible nitric oxide synthase (iNOS) mediated triple negative breast cancer progression

Abstract Human endogenous retrovirus K (HERV-K) belongs to a family of endogenous retroviruses that are present in our genome with similarities to present day exogenous retroviruses. This virus can express several proteins but our knowledge of HERV-K expression in human cancers is mainly limited to the envelope (Env) protein. Elevated HERV-K env protein expression has been shown in breast cancer both in in vitro and in vivo studies. This project aimed to decipher mechanisms of HERV-K induction in triple negative breast cancer (TNBC), and the impact of HERV-K targeting shRNA mediated knockdown on TNBC characteristics including cell migration, invasion and proliferative capacity in 2D and 3D cell culture models. Our results show that a role for inducible nitric oxide synthase (iNOS) in the induction of HERV-K in TNBC cell lines. RNA seq and bioinformatics analysis was performed to identify key molecular processes regulated by HERV-K and nitric oxide (NO) in MDA-MB-231 TNBC cells. Reduced rates of migration, invasion and proliferation in HERV-K knockdowns points towards the essential role of HERV-K in tumorigenesis and metastasis. HERV-K knockdown also modulated key gene expression signatures traditionally associated with the basal and mesenchymal phenotypes in breast cancer, cellular senescence and MHC class gene regulation. The co-expression of iNOS and HERV-K was assessed in over 150 TNBC cases and the association with patient outcomes assessed. Taken together, our findings indicate that NO and HERV-K may be a useful molecular target for the treatment of TNBC. Citation Format: Dibyangana Bhattacharyya, Eoin Dervan, Sharon Glynn, Grace Callagy. Unravelling the role of human endogenous retrovirus K (HERV-K) in inducible nitric oxide synthase (iNOS) mediated triple negative breast cancer progression [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-25.

Human Endogenous Retroviruses in Diseases.

Human endogenous retroviruses (HERVs), which are conserved sequences of ancient retroviruses, are widely distributed in the human genome. Although most HERVs have been rendered inactive by evolution, some have continued to exhibit important cytological functions. HERVs in the human genome perform dual functions: on the one hand, they are involved in important physiological processes such as placental development and immune regulation; on the other hand, their aberrant expression is closely associated with the pathological processes of several diseases, such as cancers, autoimmune diseases, and viral infections. HERVs can also regulate a variety of host cellular functions, including the expression of protein-coding genes and regulatory elements that have evolved from HERVs. Here, we present recent research on the roles of HERVs in viral infections and cancers, including the dysregulation of HERVs in various viral infections, HERV-induced epigenetic modifications of histones (such as methylation and acetylation), and the potential mechanisms of HERV-mediated antiviral immunity. We also describe therapies to improve the efficacy of vaccines and medications either by directly or indirectly targeting HERVs, depending on the HERV.

Expression Profiles of Human Endogenous Retrovirus in Chronic Myeloid Leukemia at Diagnosis and after TKI Therapy

INTRODUCTION Chronic Myeloid Leukemia (CML) has become a manageable and possibly curable disease due to the use of Tyrosine Kinase inhibitors (TKI). Although the immune system has been shown to be dysfunctional in newly diagnosed CML patients, TKI therapy may restore the function of the immune cells, and thus, the immune system may play a role in the leukemia control. In this complex immune interplay, the modulation and possible role of Human Endogenous Retroviruses (HERVs) expression is still poorly characterized. HERVs represent ~8% of the human genome and have been repeatedly domesticated by the host for major physiological functions, such as the development of placenta and the shaping of complex networks, including the main antiviral pathways of innate immunity. Accordingly, HERVs are still able to both modulate and be influenced by the host immune system and are thus highly investigated in several pathological contexts of immune dysregulation, such as autoimmunity and cancer. The aim of this study was to evaluate the overall HERV transcription profile in CML patients as compared to healthy controls (HC), to explore the regulatory influence of HERVs and their links to CML immune pathogenesis. METHODS The analysis included 10 HC and a total of 23 CML (11 Male, 7 Female, age range 45-84) being either at diagnosis (5 patients) or after TKI treatment (18 patients) for a minimum of 24 months and a molecular response of MR3 or deeper. Total RNA from peripheral blood cells was deep sequenced to obtain transcriptomic profiles, analyzed for the set of HERVs (~3300) and cellular genes (~60700) expression. RESULTS HERV transcriptome is significantly modulated in CML patients, clearly dividing them from HC. In addition, among CML patients, specific signatures of HERV modulation allows to distinguish actively affected patients from the ones that are in molecular remission after TKI treatment. The latter are also very different from HC in terms of HERV expression, possibly due to residual modulation by the disease and/or the prosecution of TKI therapy. Differential expression analyses allowed to identify a total of 575 and 568 deHERVs significantly modulated between CML patients at diagnosis and HC and between CML treated patients in molecular remission (MR3-MR5) and HC (padj: 3.36e-96 to 0.0098 and 8.32e-69 to 0.0099, respectively). In addition, 267 deHERVs were found comparing the same CML patients at diagnosis and during remission (padj: 5.55e-81 to 0.0099). The differential human gene expression revealed about 5800 dysregulated genes (4782 up and 1019 down, padj: 3.96e-260 to 9.5e-30) in CML pts vs HC. The top overexpressed genes were DDX17, VPS13B, PHIP, SMG1, STK10, LRRFIP1 with under-regulation of RNF213, MIR1276, ZRANB2-AS1, AC138028.4 genes, among others. Pairwise comparisons of 5 CML at diagnosis vs samples after treatment with imatinib resulted in a downregulation of ZNF831, EVL, TXK, HAPLN3, SEPTIN1, TNFRSF25 and upregulation of LTF, MPO, ABCA13, BPI, BCL2L15, ERG, MMP8, DEFA4, ANLN, SCN9A genes. CONCLUSIONS The present study provides the first high-throughput snapshot of HERV transcriptome in CML and identify specific sets of HERVs that can distinguish patients at diagnosis, patients in molecular response to TKI therapies and HC. Patient's gene expression profiles revealed that during molecular remission and under continuous treatments is present a disregulated pathway that is different from healthy individuals. Our results can give insights on the role of HERVs in the biology of CML and may add information useful to select the most effective pathways to target to maximize an advantageous immune response and promote a successful TKI discontinuation. Moreover, the following question is open: is there a potential regulatory role of HERVs in the genomic balance of CML patients? Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Single-cell RNA sequencing highlights the functional role of human endogenous retroviruses in gallbladder cancer.

Gallbladder cancer (GBC), the most common malignancy of the biliary tract, shows late diagnosis and low survival rate and requires continued search for new diagnostic biomarkers and therapeutic targets. Human endogenous retroviruses (HERVs) are specifically prone to be reactivated in diverse cancers and are implicated in cancer progression and immunotherapy. Single-cell RNA sequencing was performed on tumor tissues and paired adjacent tissues from 4 GBC patients. Dual-luciferase reporter assay was applied to measure enhancer activity of HERV sequences. We dissected the cellular diversity and described the HERV transcriptomic landscape for GBC. We found that HERVs were transcribed in a cell type-specific manner and different HERV families were associated with diverse biological effects. HERVs could function as enhancers, presumably causing altered expression of neighboring genes. The transcription level of HERVH was gradually elevated with the malignant transformation of epithelial cells, suggesting HERVH may be a potential early diagnostic biomarker of GBC. HHLA2, a newly emerging immune checkpoint, was derived by HERVH, exhibited an expressional correlation with HERVH, and was identified as a promising target for immunotherapy. Exploring the transcriptional landscape and potential functional impact of HERVs highlights the important role of HERVs in GBC and provides a fresh perspective on managing GBC. This study was supported by the National Natural Science Foundation of China (31970176, 81972256) and the research grants from the Innovation Capacity Building Project of Jiangsu province (BM2020019).

Human endogenous retroviruses in viral disease and therapy

AbstractAs retained sequences of ancient retroviruses, human endogenous retroviruses (HERVs) are widespread in the human genome. Although most HERVs have been inert throughout evolution, several HERVs are still functional and involved in various diseases, such as autoimmune diseases, cancer, neurological diseases and viral infection. Hence, certain types of therapies targeting HERVs or utilizing HERV tools have been developed. Here, we summarize recent findings on the role of HERVs in viral infection, including HERV dysregulation in different kinds of viral infections and the potential mechanisms of HERV‐mediated antiviral immunity. In addition, we provide an overview of HERV‐related therapies that directly target HERVs or are indirectly based on HERVs to improve the efficacy of vaccines and drugs.

Senescent cells and cancer cells as apoptosis suppressors: Causes and effects

The death of some senescent cells (KS), as well as neoplastic cells (KN), can be paradoxically inhibited at the stage of apoptosis. Thus, the KS become inhibitors of oncogenesis at the beginning of the phenomenon. The influence of KS and KN on the inhibition of apoptosis is multidirectional, which is presented graphically in the form of Euler’s mathematical circles (Fig. 2). Senescence, like apoptosis, may to some extent inhibit oncogenesis. The neoplastic process is also associated with non-apoptotic death, i.e. entosis, as well as autophagy, i.e. autophagocytosis with the participation of lysosomes. The process of autophagy may also involve the cell proteolytic system via the ubiquitin-proteasome system (UPS), in which polyubiquitination of suppressor proteins, e.g. p53 protein, leads to oncogenesis. Therefore, both of the above-mentioned processes of autophagy favour oncogenesis. The paper also presents the role of human endogenous retroviruses (HERs) in oncogenesis, with particular emphasis on the syncytin gene and its participation in the induction of placental cancer (choriocarcinoma, chorioepithelioma).

The Roles of Human Endogenous Retroviruses (HERVs) in Inflammation

<p>Human endogenous retroviruses (HERVs) are ancient, currently inactive, and non-infectious due to recombination, deletions, and mutations in the host genome. However, HERV-derived elements are involved in physiological phenomena including inflammatory response. In recent studies, HERV-derived elements were involved directly in various inflammatory diseases including autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Sjogren’s syndrome. Regarding the involvement of HERV-derived elements in inflammation, two possible mechanisms have been proposed. First, HERV-derived elements cause nonspecific innate immune processes. Second, HERV-derived RNA or proteins might stimulate selective signaling mechanisms. However, it is unknown how silent HERV elements are activated in the inflammatory response and what factors and signaling mechanisms are involved with HERV-derived elements. In this review, we introduce HERV-related autoimmune diseases and propose the possible action mechanisms of HERV-derived elements in the inflammatory response at the molecular level.</p>

Viral Causality of Human Cancer and Potential Roles of Human Endogenous Retroviruses in the Multi-Omics Era: An Evolutionary Epidemiology Review.

Being responsible for almost 12% of cancers worldwide, viruses are among the oldest known and most prevalent oncogenic agents. The quality of the evidence for the in vivo tumorigenic potential of microorganisms varies, thus accordingly, viruses were classified in 4 evidence-based categories by the International Agency for Research on Cancer in 2009. Since then, our understanding of the role of viruses in cancer has significantly improved, firstly due to the emergence of high throughput sequencing technologies that allowed the “brute-force” recovery of unknown viral genomes. At the same time, multi-omics approaches unravelled novel virus-host interactions in stem-cell biology. We now know that viral elements, either exogenous or endogenous, have multiple sometimes conflicting roles in human pathophysiology and the development of cancer. Here we integrate emerging evidence on viral causality in human cancer from basic mechanisms to clinical studies. We analyze viral tumorigenesis under the scope of deep-in-time human-virus evolutionary relationships and critically comment on the evidence through the eyes of clinical epidemiology, firstly by reviewing recognized oncoviruses and their mechanisms of inducing tumorigenesis, and then by examining the potential role of integrated viruses in our genome in the process of carcinogenesis.

Abstract 1332: Antiretroviral agent inhibits proliferation and motility of BT-20 cells through inhibition of human endogenous retrovirus type K

Abstract The purpose of the study was to establish the role of human endogenous retrovirus K (HERV-K) in cancer development and to explore the possibility of repurposing antiretroviral agents for cancer treatment. We screened different categories of antiretroviral agents and several breast cancer cell lines to study the ability of antiretroviral agents to inhibit cancer cell proliferation and to inhibit the natural expression of HERV-K in cancer cells. Cells were transduced with exogenous HERV-K genes or with HERV-K knockdown plasmids to investigate the relationship between cytotoxic effect of antiretroviral agents and HERV expression. We found that an integrase strand-transfer inhibitor, dolutegravir, inhibited HERV-K expression on both the RNA and protein levels in BT-20 cells. Transduction with both HERV-K env and pol genes rendered the cell line more resistant to dolutegravir. Knockdown of HERV-K with shRNA also increased resistance to dolutegravir compared to cells transduced with random double-stranded RNA. The cytotoxic effect of dolutegravir correlated with enhanced expression of E-cadherin and a reduction in cell motility. Interestingly, an HERV-K knockdown cell line also exhibited enhanced expression of E-cadherin and reduced motility. As a potential carcinogenic role of HERVs has raised interest in using antiretroviral agents as a new approach to treat cancer, we provide the first evidence that one antiretroviral agent actually inhibits the proliferation and motility of a cancer cell line through inhibiting an HERV. Citation Format: John Lin, Mason Farris, Lauren Robbins, Matthew Lee, Serratt Nong, Yingguang Liu. Antiretroviral agent inhibits proliferation and motility of BT-20 cells through inhibition of human endogenous retrovirus type K [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1332.

The role of human endogenous retroviruses in gliomas: from etiological perspectives and therapeutic implications.

Accounting for approximately 8% of the human genome, human endogenous retroviruses (HERVs) have been implicated in a variety of cancers including gliomas. In normal cells, tight epigenetic regulation of HERVs prevent aberrant expression; however, in cancer cells, HERVs expression remains pervasive, suggesting a role of HERVs in oncogenic transformation. HERVs may contribute to oncogenesis in several ways including insertional mutagenesis, chromosomal rearrangements, proto-oncogene formation, and maintenance of stemness. On the other hand, recent data has suggested that reversing epigenetic silencing of HERVs may induce robust anti-tumor immune responses, suggesting HERVs' potential therapeutic utility in gliomas. By reversing epigenetic modifications that silence HERVs, DNA methyltransferase, and histone deacetylase inhibitors may stimulate a viral-mimicry cascade via HERV-derived dsRNA formation that induces interferon-mediated apoptosis. Leveraging this anti-tumor autoimmune response may be a unique avenue to target certain subsets of epigenetically-dysregulated gliomas. Nevertheless, the role of HERVs in gliomas as either arbitrators of oncogenesis or forerunners of the innate anti-tumor immune response remains unclear. Here, we review the role of HERVs in gliomas, their potential dichotomous function in propagating oncogenesis and stimulating the anti-tumor immune response, and identify future directions for research.

Genomic Study of COVID-19 Corona Virus Excludes Its Origin from Recombination or Characterized Biological Sources and Suggests a Role for HERVS in Its Wide Range Symptoms.

The COVID-19 corona virus has become a world pandemic which started in December 2019 in Wuhan, China with no confirmed biological source. Various countries reported the genomic sequence of different isolates obtained from infected patients. This allowed us to obtain a number of 38 isolates of full genomic sequences. Alignment of nucleotide (nt) sequence was carried out using Clustal Omega multiple alignment service at the EBI website. Alignment of nt sequence and phylogenetic relationship revealed that the COVID-19 is a new viral strain and its biological source has not been yet detected. The expected orf pattern was different among isolates obtained from the same country or different countries as well as from SARS-CoV isolates or bats CoV suggesting different virus human interaction possibilities during infection and severity. All isolates had the main five orfs (1ab, S, M, N, E), whereas they differed in the expected accessory orfs. Being with the biological source of COVID-19 undetected, the role of human endogenous retrovirus (HERVs) in the regulation of the host cell gene expression or the encoding for products that could modulate COVID-19 infection and the spectrum of its symptoms is discussed.

Human Endogenous Retrovirus Expression Is Upregulated in the Breast Cancer Microenvironment of HIV Infected Women: A Pilot Study.

In people living with HIV (PLWH), chronic inflammation can lead to cancer initiation and progression, besides driving a dysregulated and diminished immune responsiveness. HIV infection also leads to increased transcription of Human Endogenous Retroviruses (HERVs), which could increase an inflammatory environment and create a tumor growth suppressive environment with high expression of pro-inflammatory cytokines. In order to determine the impact of HIV infection to HERV expression on the breast cancer microenvironment, we sequenced total RNA from formalin-fixed paraffin-embedded (FFPE) breast cancer samples of women HIV-negative and HIV-positive for transcriptome and retrotranscriptome analyses. We performed RNA extraction from FFPE samples, library preparation and total RNA sequencing (RNA-seq). The RNA-seq analysis shows 185 differentially expressed genes: 181 host genes (178 upregulated and three downregulated) and four upregulated HERV transcripts in HIV-positive samples. We also explored the impact of HERV expression in its neighboring breast cancer development genes (BRCA1, CCND1, NBS1/NBN, RAD50, KRAS, PI3K/PIK3CA) and in long non-coding RNA expression (AC060780.1, also known as RP11-242D8.1). We found a significant positive association of HERV expression with RAD50 and with AC060780.1, which suggest a possible role of HERV in regulating breast cancer genes from PLWH with breast cancer. In addition, we found immune system, extracellular matrix organization and metabolic signaling genes upregulated in HIV-positive breast cancer. In conclusion, our findings provide evidence of transcriptional and retrotranscriptional changes in breast cancer from PLWH compared to non-HIV breast cancer, including dysregulation of HERVs, suggesting an indirect effect of the virus on the breast cancer microenvironment.

Human Endogenous Retrovirus Expression Is Associated with Head and Neck Cancer and Differential Survival.

Human endogenous retroviruses (HERVs) have been implicated in a variety of human diseases including cancers. However, technical challenges in analyzing HERV sequence data have limited locus-specific characterization of HERV expression. Here, we use the software Telescope (developed to identify expressed transposable elements from metatranscriptomic data) on 43 paired tumor and adjacent normal tissue samples from The Cancer Genome Atlas Program to produce the first locus-specific retrotranscriptome of head and neck cancer. Telescope identified over 3000 expressed HERVs in tumor and adjacent normal tissue, and 1078 HERVs were differentially expressed between the two tissue types. The majority of differentially expressed HERVs were expressed at a higher level in tumor tissue. Differentially expressed HERVs were enriched in members of the HERVH family. Hierarchical clustering based on HERV expression in tumor-adjacent normal tissue resulted in two distinct clusters with significantly different survival probability. Together, these results highlight the importance of future work on the role of HERVs across a range of cancers.