Human endogenous retroviruses and cancer:Causality and therapeutic possibilities

A substantial part of the human genome is derived from transposable elements;remnants of ancient retroviral infections.Conservative estimates set the percentage of human endogenous retroviruses(HERVs) in the genome at 8%.For the most part,the interplay between mutations,epigenetic mechanisms and posttranscriptional regulations silence HERVs in somatic cells.We first highlight mechanisms by which activation of members of several HERV families may be associated with tumor development before discussing the arising chances for both diagnosis and therapy.It has been shown that at least in some cases,tumor cells expressing HERV open reading frames(ORFs) thus gain tumor-promoting functions.However,since these proteins are not expressed in healthy tissues,they become prime target structures.Of potential pharmacological interest are the prevention of HERV transposition,the inhibition of HERV-encoded protein expression and the interference with these proteins' activities.Evidence from recent studies unequivocally proves that HERV ORFs represent a very interesting source of novel tumor-specific antigens with even the potential to surpass entity boundaries.The development of new tumor(immune-) therapies is a very active field and true tumor-specific targets are of outstanding interest since they minimize the risk of autoimmunity and could reduce side effects.Finally,we postulate on main future research streams in order to stimulate discussion on this hot topic.

Human leukemia antigen-A0201-restricted epitopes of humanendogenous retrovirus W family envelope(HERV-W env)inducestrong cytotoxic T lymphocyte responses

Human endogenous retrovirus W family(HERV-W) envelope(env) has been reported to be related to several human diseases, including autoimmune disorders, and it could activate innate immunity.However, there are no reports investigating whether human leukemia antigen(HLA)-A~*0201^+restriction is involved in the immune response caused by HERV-W env in neuropsychiatric diseases. In the present study, HERV-W env-derived epitopes presented by HLA-A~*0201 are described with the potential for use in adoptive immunotherapy. Five peptides displaying HLAA~*0201-binding motifs were predicted using SYFEPITHI and BIMAS, and synthesized. A CCK-8 assay showed peptides W, Q and T promoted lymphocyte proliferation. Stimulation of peripheral blood mononuclear cells from HLA-A~*0201^+ donors with each of these peptides induced peptidespecific CD8^+ T cells. High numbers of IFN-γ-secreting T cells were also detectable after several weekly stimulations with W, Q and T. Besides lysis of HERV-W env-loaded target cells, specific apoptosis was also observed. These data demonstrate that human T cells can be sensitized toward HERV-W env peptides(W, Q and T) and, moreover, pose a high killing potential toward HERV-W env-expressing U251 cells. In conclusion, peptides W Q and T, which are HERV-W env antigenic epitopes, have both antigenicity and immunogenicity, and can cause strong T cell immune responses. Our data strengthen the view that HERV-W env should be considered as an autoantigen that can induce autoimmunity in neuropsychiatric diseases, such as multiple sclerosis and schizophrenia. These data might provide an experimental foundation for a HERV-W env peptide vaccine and new insight into the treatment of neuropsychiatric diseases.

Human Endogenous Retroviruses as Biomedicine Markers

Human endogenous retroviruses(HERVs)were formed via ancient integration of exogenous retroviruses into the human genome and are considered to be viral“fossils”.The human genome is embedded with a considerable amount of HERVs,witnessing the long-term evolutionary history of the viruses and the host.Most HERVs have lost coding capability during selection but still function in terms of HERV-mediated regulation of host gene expression.In this review,we summarize the roles of HERV activation in response to viral infections and diseases,and emphasize the potential use of HERVs as biomedicine markers in the early diagnosis of diseases such as cancer,which provides a new perspective for the clinical application of HERVs.

Human Endogenous Retroviruses and Hematological Malignant Tumors

Human endogenous retrovirus(HERV)gene sequences are remnants of retroviruses that infected the ancestors of humans millions of years ago and were integrated into human chromosomes,accounting for approximately 8%-9%of the human genome.Most integrated HERVs have lost their coding capacity and remain silent due to frame shifts,mutations,and sequence deletions or insertions over the millions of years,but their expression is highly regulated by epigenetic and host defense mechanisms.However,there are still some HERV genes that have intact open reading frames due to recent integration into the human genome or positive selective pressure.The abnormal activation of HERVs may contribute to diseases or their pathology,such as malignant tumors,autoimmune diseases,and nervous system diseases.The occurrence and development of hematological malignant tumors(HMTs)is a complex process involving interactions of multiple genetic and environmental factors.The abnormal activation of HERVs may contribute to the pathology of HMTs via indirect mechanisms.In this review,we address the discovery of endogenous retroviruses in vertebrates,and the classification and genomic structure of HERVs.Among HERV family members,HERV-K is the latest type of HERV integrated into the human genome and it has the strongest transcriptional activity.We explore the currently known expression of HERV-K proto-oncogenes in HMTs and further address potential research and therapeutic approaches.However,much remains to be learned about not only the impact of HERVs on the occurrence of HMTs,but also the potential value of HERVs as diagnostic and therapeutic targets for HMTs.

HERV-K与白血病的关系

人类基因组8%是由逆转录病毒基因组成。人内源性逆转录病毒(human endogenous retrovirus,HERV)是外源性逆转录病毒感染人类并整合到人类基因组中,以孟德尔遗传定律遗传下来的残余物。其中HERV-K是HERV中最完整的具有开放阅读框的病毒家族,与白血病等肿瘤的发生发展相关。本文将介绍HERV-K与白血病发生之间的关系。

基于生物信息学的HERV研究现状与发展趋势

近年来研究证实,人内源性逆转录病毒(HERV)中长末端重复序列(LTR)和囊膜蛋白基因(env)与基因异常表达关系密切。本文阐述了HERV国内外研究现状与发展动态。从生物信息学角度对LTR中启动子、多聚腺苷化(PolyA)信号和增强子等顺式作用元件以及env中的免疫抑制区(ISD)进行了重点分析。指出上述元件和潜在功能区在基因的异常表达和囊膜蛋白的免疫抑制中起关键作用,必将成为HERV与基因异常表达关系研究的热点与趋势。通过此类研究,以期为癌症疾病的早期诊断和治疗靶位点的选择奠定理论基础。

新的含有11q13.5HERV-Wgag序列的内含子转录子的鉴定

目的:鉴定位于染色体11q13.5的含有HERV-Wgag序列的内含子转录子,探讨这一新的转录子对宿主基因PTD015选择性剪切的调控作用。方法:采用半巢式PCR和降落PCR扩增目的片段,克隆、测序、构建载体、转染JEG3细胞,采用实时PCR检测PTD015选择性剪切mRNA的水平。结果:鉴定了一个位于基因PTD015第二内含子上长1739bp的转录子,该转录子包含755bp11q13.5HERV-Wgag序列、527bp5′长末端重复序列和11q13.5HERV-W5′端457bp片段。此内含子反义转录子质粒的转染使JEG3细胞PTD015选择性剪切mRNA的水平明显降低。结论:源于基因PTD015第二内含子含有HERV-Wgag序列的反义转录子可调节宿主基因PTD015的选择性剪切。

新基因HERV-H-X的env区分析及其在结肠癌组织中的表达

背景与目的:我们在结肠癌组织中发现了一个新的基因HERV-H-X。本研究的目的是分析HERV-H-Xenv区的缺失情况,研究其与其他HERV-Henv开放阅读框(open reading frames,ORF)的表达关系以及其在结肠癌与正常组织中的表达差异情况。方法:对HERV-H-X与含完整的envORF的HERV-H/env62、HERV-H/env60以及HERV-H/env59进行多序列比对,分析HERV-H-Xenv区的缺失情况。对HERV-H-X设计特异的引物,对HERV-H/env62、env60以及env59的envORF设计共同的引物,分别在8对结肠癌与相应癌旁正常组织中进行RT-PCR,比较它们的表达情况。对HERV-H-X进行实时荧光定量PCR,研究其在17对结肠癌与相应正常组织中的表达水平。结果:HERV-H-Xenv区缺失的序列正好相应于HERV-H/env62、env60以及env59的envORF区。RT-PCR结果显示HERV-H-X特异地在结肠的癌组织中表达,而HERV-Henv的ORF在结肠的癌组织与正常组织中都有表达。定量PCR结果显示HERV-H-X在结肠癌组织的平均表达水平是相应正常组织的24.9倍,经F检验证实差异有统计学意义(P<0.01)。结论:HERV-H-X的表达与结肠癌特异相关,但由于缺失env的ORF,其在结肠癌的高表达与env基因无关。

用巢式RT-PCR检测精神分裂症患者血液标本中HERV env基因

The association between transcriptional activation of HERV and the develop- ment of schizophrenia was investigated. Nested RT-PCR was used to detect the preval- ence of HERV env RNA in the PBMCs of individuals with recent-onset of schizophrenia and normal persons from central and southern China. β-actin gene was used as an internal control. HERV env homologous sequences were found in the PBMCs of 8 of 28 (28.6%) individuals with recent-onset schizophrenia, while no env sequences were identified in any of the PBMCs obtained from 24 normal person (P<0.001). The results suggested that transcriptional activation of HERV might be associated with the develop- pment of schizophr- enia in at least some patients.

Human endogenous retrovirus W env increases nitric oxide production and enhances the migration ability of microglia by regulating the expression of inducible nitric oxide synthase

Human endogenous retrovirus W env(HERV-W env) plays a critical role in many neuropsychological diseases such as schizophrenia and multiple sclerosis(MS). These diseases are accompanied by immunological reactions in the central nervous system(CNS). Microglia are important immunocytes in brain inflammation that can produce a gasotransmitter – nitric oxide(NO). NO not only plays a role in the function of neuronal cells but also participates in the pathogenesis of various neuropsychological diseases. In this study, we reported increased NO production in CHME-5 microglia cells after they were transfected with HERV-W env. Moreover, HERV-W env increased the expression and function of human inducible nitric oxide synthase(hi NOS) and enhanced the promoter activity of hi NOS. Microglial migration was also enhanced. These data revealed that HERV-W env might contribute to increase NO production and microglial migration ability in neuropsychological disorders by regulating the expression of inducible NOS. Results from this study might lead to the identification of novel targets for the treatment of neuropsychological diseases, including neuroinflammatory diseases, stroke, and neurodegenerative diseases.

Transcriptome Analyses Implicate Endogenous Retroviruses Involved in the Host Antiviral Immune System through the Interferon Pathway

Human endogenous retroviruses(HERVs) are the remains of ancient retroviruses that invaded our ancestors’ germline cell and were integrated into the genome. The expression of HERVs has always been a cause for concern because of its association with various cancers and diseases. However, few previous studies have focused on specific activation of HERVs by viral infections. Our previous study has shown that dengue virus type 2(DENV-2) infection induces the transcription of a large number of abnormal HERVs loci;therefore, the purpose of this study was to explore the relationship between exogenous viral infection and HERV activation further. In this study, we retrieved and reanalyzed published data on 21 transcriptomes of human cells infected with various viruses. We found that infection with different viruses could induce transcriptional activation of HERV loci. Through the comparative analysis of all viral datasets, we identified 43 key HERV loci that were up-regulated by DENV-2, influenza A virus, influenza B virus, Zika virus, measles virus, and West Nile virus infections. Furthermore, the neighboring genes of these HERVs were simultaneously up-regulated, and almost all such neighboring genes were interferon-stimulated genes(ISGs), which are enriched in the host’s antiviral immune response pathways. Our data supported the hypothesis that activation of HERVs, probably via an interferon-mediated mechanism, plays an important role in innate immunity against viral infections.

DNA低甲基化与系统性红斑狼疮关系的研究进展

当各种原因引起T细胞DNA低甲基化后,对自身免疫有潜在作用的基因表达增加。CD 70过度表达可能与B细胞的活化、免疫球蛋白的分泌有关。perforin可能在T细胞介导的单核巨噬细胞凋亡中起重要作用。DNA低甲基化可使人类的内源性逆转录病毒序列活化,表达的抗原可以诱导机体产生自身抗体。多胺改变了染色体的正常结构,干扰了DNA的甲基化过程,在自身免疫性疾病中的发病作用近来引起了人们的关注。

人内源性逆转录病毒K包膜蛋白在乳腺肿瘤组织中的表达及意义

目的:检测人内源性逆转录病毒K(HERV-K)包膜蛋白(env蛋白)在不同乳腺肿瘤组织中的表达,分析其表达水平与乳腺癌患者临床病理特征的相关性,探讨HERV-K env蛋白的表达与乳腺癌预后的关系。方法:免疫组织化学法检测HERV-Kenv蛋白在95例乳腺癌组织、30例乳腺良性肿瘤组织中的表达情况,x^2检验用于分析HERV-K env蛋白的表达水平与乳腺癌患者临床病理特征的相关性。结果:免疫组织化学结果显示,HERV-K env蛋白的阳性表达主要位于细胞浆,该蛋白在乳腺癌组织中多呈强阳性或中度阳性表达,而在乳腺良性肿瘤组织中多呈阴性或弱阳性表达。HERV-K env蛋白在乳腺癌组织中的阳性表达率(88.4%)明显高于乳腺良性肿瘤组织(40.0%),差异具有统计学意义(P<0.001)。HERV-K env蛋白的表达水平与乳腺癌的某些预后因素存在相关性。在HERV-K env蛋白表达阳性的乳腺癌患者中,该蛋白的表达水平与肿瘤大小、临床分期、腋窝淋巴结转移数目之间存在正相关关系,与ER的表达状况之间存在负相关关系(P均<0.05),而与患者的年龄、组织学分级以及PR的表达状况无相关性(P均>0.05)。结论:HERV-K env蛋白在乳腺良性肿瘤中多为阴性表达,而在乳腺癌中多呈阳性表达,并且可能与乳腺癌的发展及预后相关,该蛋白在乳腺癌中的表达水平可能是一种判断乳腺癌预后的指标。

内源性逆转录病毒长末端重复序列在嗜酸性粒细胞增多症的基因表达及核苷酸序列分析

探索人内源性逆转录病毒长末端重复序列(LTR)基因及表达与嗜酸性粒细胞增多症发生的关系。PCR法检测嗜酸性粒细胞增多症患者外周血中内源性逆转录病毒长末端重复序列基因,RT-PCR法检测内源性逆转录病毒基因表达。变性高效液相分析和序列测定LTR片段核苷酸序列,对不同株基因序列作同源性的比较分析。PCR结果显示:20例嗜酸性粒细胞增多症患者细胞中均获得内源性逆转录病毒长末端重复序列扩增产物,嗜酸性粒细胞增多症组中长末端重复序列基因有高的表达,而正常人表达为阴性。与HERV-K家族LTR基因相应区域核苷酸序列比较;嗜酸性粒细胞增多组长末端重复序列U3、R、U5区同源性分析有核苷酸的改变,与淋巴瘤对照比较没有大片段的缺失。人类基因组中普遍存在逆转录病毒长末端重复序列。正常人和嗜酸性粒细胞增多症患者中长末端重复序列有不同程度核苷酸碱基的变异,但是,二者比较,这种改变与嗜酸性粒细胞的增多没有明显的相关性。在嗜酸性粒细胞增多症患者中有高的基因表达而正常人中没有可检出的病毒基因的表达,嗜酸粒细胞的增多可能与逆转录病毒基因表达水平有关,其诱导嗜酸粒细胞增多的机制需进一步的研究。

人内源性逆转录病毒研究概况

人类内源性逆转录病毒（HERV）是几百万年前整合到人类基因组中的逆转录病毒的残余物，约占了整个基因组的8％。大部分HERV元件在进化过程中由于突变、缺失等的积累,已没有编码能力。但仍有少数由于正性选择的压力，完整的开放阅读框被保留了下来。它们在一些特定的组织或分化发育的特定阶段表面，可能具有重要的生理意义。而在某些疾病情况下的高表达水平提示其可能与疾病的发生发展相关。由于最初插入位点的关系或后来的转座作用，HERV元件相互之间以及对基因组中的其他基因都可能有影响。对HERV目前还了解甚少，该文将对HERV的生物学功能以及对HERV-K、-W、-H3个家族的研究概况作一简要综述。

病毒化石人内源性反转录病毒对于肿瘤诊断治疗的意义

人内源性反转录病毒(human endogenous retrovirus,HERV)从人类祖先时期就整合入人类基因组,一直被认为是无用的垃圾序列。然而随着现代科学的发展其与人类进化、发育及一些疾病的进程都有着千丝万缕的联系。HERV信使RNA、蛋白质及有缺陷的病毒颗粒都可能与疾病的发生及进程相关。作者以HERV的相关研究热点之一HERV-K与肿瘤的关系为切入点,全面地对近5年为主的文献资料进行分析总结,综述HERV的生物学特性、致病机制、近期实验的进展及生物信息学对于HERV的探索,深入分析和展现HERV对肿瘤病理分析的重要性和临床应用的价值,为致病机制复杂肿瘤提供一个新的病理分析方向和诊断治疗标准。

人内源性逆转录病毒W家族与疾病相关性的研究

人内源性逆转录病毒(human endogenous retroviruses,HERV)是几百万年前整合至人类基因组并遗传至今的外源性逆转录病毒的残余物。因突变、缺失等导致大多数HERV没有完整的开放读码框,但仍有部分家族成员可编码完整的病毒蛋白,如分离自多发性硬化症患者的γ逆转录病毒相似元件家族成员HERV-W的包膜蛋白基因(HERV-W env,又称ERVWE1)编码的ENV蛋白(又称Syncytin-1),在人胎盘发育过程中起细胞融合以及免疫调节作用。在生理条件下,HERV-W受到表观遗传调控而其转录活性被抑制;但亦可被环境、遗传等因素激活,如自身免疫性疾病、精神疾病及癌症等。研究发现HERV-W可能在疾病的发生、发展中起重要的“桥梁”与“触发”作用,靶向Syncytin-1的单克隆抗体GNbAC1已用于多发性硬化症的临床研究,并且在1型糖尿病中也有良好的应用前景。对HERV-W的深入研究可为某些疾病的诊断和治疗提供重要的途径。

Domesticated HERV-W env contributes to the activation of the small conductance Ca^(2+)-activated K^(+)type 2 channels via decreased 5-HT4 receptor in recent-onset schizophrenia

The human endogenous retroviruses type W family envelope(HERV-W env)gene is located on chromosome 7q21-22.Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase cal-cium influx.Additionally,the 5-HTergie system and particularly 5-hydroxytryptamine(5-HT)receptors play a prominent role in the pathogenesis and treatment of schizophrenia.5-hydroxytryptamine receptor 4(5-HT4R)agonist can block calcium channels.However,the underlying relationship between HERV-W env and 5-HT4R in the etiology of schizophrenia has not been revealed.Here,we used enzyme-linked immunosorbent assay to detect the concentration of HERV-W env and 5-HT4R in the plasma of patients with schizophrenia and we found that there were decreased levels of 5-HT4R and a negative correlation between 5-HT4R and HERV-W env in schizophrenia.Overexpression of HERV-W env decreased the transcription and protein levels of 5-HT4R but increased small conductance Ca^(2+)-activated K^(+)type 2 channels(SK2)expression levels.Further studies revealed that HERV-w env could interact with 5-HT4R.Additionally,luciferase assay showed that an essential region(-364 to-176 from the transcription start site)in the SK2 promoter was required for HERV-W env-induced SK2 expression.Importantly,5-HT4R participated in the regulation of SK2 expression and promoter activity.Electrophysiological recordings suggested that HERV-Wenv could increase SK2 channel currents and the increase of SK2 currents was inhibited by 5-HT4R.In condusion,HERV-W env could activate SK2 channels via decreased 5-HT4R,which might exhibit a novel mechanism for HERV-Wenv to influence neuronal activity in schizophrenia.

344例健康人基因组中人内源性逆转录病毒K103、K11、K113和K115基因分布

目的 明确人内源性逆转录病毒(HERV)-K103、HERV-K11、HERV-K113和HERV-K115基因在我国健康人群基因组中的插入率,并分析其在不同民族、性别、年龄之间的分布。方法 选择2022年1月-2023年4月在宿迁市第一人民医院体检以及新疆某部队官兵及家属344名健康体检人群为研究对象。收集体检人群的外周血淋巴细胞富集液(PBMC)样本,提取基因组DNA,通过聚合酶链式反应(PCR)扩增及核酸电泳检测,判断样本基因组中HERV-K103、HERV-K11、HERV-K113和HERV-K115基因插入状况,分析其在不同民族、性别、年龄的分布是否存在差异。结果 在本研究所收集的344份健康人PBMC样本中,HERV-K103、HERV-K11、HERV-K113和HERV-K115插入率分别为18.31%、82.56%、31.98%和10.17%。HERV-K11在汉族的插入率为96.77%高于维吾尔族(45.83%)(P<0.05);HERV-K115在汉族的插入率为4.84%,低于维吾尔族(23.96%)(P<0.05);HERV-K103和HERV-K113的插入率在汉族和维吾尔族间无统计学差异。HERV-K103、HERVK11、HERV-K113和HERV-K115在不同年龄、性别之间的分布无统计学差异。结论 首次阐明HERV-K103、HERV-K11、HERV-K113和HERV-K115基因在我国汉族和维吾尔族健康人基因组中的频率分布,为进一步研究其与癌症、自身免疫性疾病和病毒感染的相关关系奠定基础。

人内源性逆转录病毒K及其在乳腺癌诊断、治疗和预后中的研究进展

乳腺癌是威胁女性健康的常见恶性肿瘤,目前尚缺乏高效敏感的早期生物标志物。人内源性逆转录病毒(human endogenous retrovirus,HERV)作为一个古老的病毒从人类祖先时期就整合进入人类基因组,过去一直被认为是无用的序列。近年来研究表明HERV参与人类的进化,与疾病发生有关,与肿瘤存在一定联系。本文以HERV家族中的HERV-K为重点,详细阐述HERV-K与疾病的关联,以及在乳腺癌中的功能作用,探讨HERV-K作为乳腺癌早期筛查分子标志物的可能性。