1 5547 109 ROLE OF EPIGENETIC MODIFICATION IN INTERFERON TREATMENT OF HEPATITIS B VIRUS INFECTION. HUMAN HEPATITIS B VIRUS (HBV) IS A SMALL, ENVELOPED DNA VIRUS THAT CAUSES ACUTE AND CHRONIC HEPATITIS. CHRONIC HEPATITIS B (CHB) IS ASSOCIATED WITH HEPATOCELLULAR CARCINOMA PATHOGENESIS. INTERFERONS (IFNS) HAVE BEEN USED FOR THE TREATMENT OF CHB FOR A LONG TIME, WITH ADVANTAGES INCLUDING LESS TREATMENT DURATION AND SUSTAINED VIROLOGICAL RESPONSE. PRESENTLY, VARIOUS EVIDENCE SUGGESTS THAT EPIGENETIC MODIFICATION OF THE VIRAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) AND THE HOST GENOME IS CRUCIAL FOR THE REGULATION OF VIRAL ACTIVITY. THIS MODIFICATION INCLUDES HISTONE ACETYLATION, DNA METHYLATION, N6-METHYLADENOSINE, AND NON-CODING RNA MODIFICATION. IFN TREATMENT FOR CHB CAN STIMULATE MULTIPLE IFN-STIMULATED GENES FOR INHIBITING VIRUS REPLICATION. IFNS CAN ALSO AFFECT THE HBV LIFE CYCLE THROUGH EPIGENETIC MODULATION. IN THIS REVIEW, WE SUMMARIZED THE DIFFERENT MECHANISMS THROUGH WHICH IFN-ALPHA INHIBITS HBV REPLICATION, INCLUDING EPIGENETIC REGULATION. MOREOVER, THE MECHANISMS UNDERLYING IFN ACTIVITY ARE DISCUSSED, WHICH INDICATED ITS POTENTIAL AS A NOVEL TREATMENT FOR CHB. IT IS PROPOSED THAT EPIGENETIC CHANGES SUCH AS HISTONE ACETYLATION, DNA METHYLATION, M6A METHYLATION COULD BE THE TARGETS OF IFN, WHICH MAY OFFER A NOVEL APPROACH TO HBV TREATMENT. 2022 2 6337 31 THE ROLE OF DNA-METHYLTRANSFERASES IN THE LIFE CYCLE OF HEPATITIS B VIRUS AND PATHOGENESIS OF CHRONIC HEPATITIS B. CHRONIC HEPATITIS B IS CAUSED BY A PERSISTENT FORM OF HEPATITIS B VIRUS, COVALENTLY CLOSED CIRCULAR DNA (CCCDNA). STABILITY OF CCCDNA IS ASSOCIATED WITH INTRACELLULAR LOCALIZATION OF CCCDNA AND FORMATION OF MINICHROMOSOME, REGULATED BY EPIGENETIC MECHANISMS. ONE OF THE KEY MECHANISMS IN EPIGENETICS IS METHYLATION OF DNA ON CPG ISLANDS. EXPRESSION LEVELS OF DNA-METHYLTRANSFERASES (DNMTS) IN CHRONIC HEPATITIS B PATIENTS WERE SHOWN TO BE UPREGULATED. NEVERTHELESS, THE ROLE OF DNMTS IN THE LIFE CYCLE OF HBV AND THEIR EFFECTS ON THE CELL REMAIN ELUSIVE. IN THIS REVIEW, WE DISCUSS LATEST ACHIEVEMENTS ON THE ROLE OF DNMTS IN CHRONIC HEPATITIS B AND HBV IN VITRO MODELS. 2018 3 6016 37 THE ASSOCIATION BETWEEN HEPATOCARCINOGENESIS AND INTRACELLULAR ALTERATIONS DUE TO HEPATITIS B VIRUS INFECTION. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A WORLDWIDE HEALTH PROBLEM LEADING TO SEVERE LIVER DYSFUNCTION, INCLUDING LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. ALTHOUGH CURRENT ANTIVIRAL THERAPIES FOR CHRONIC HBV INFECTION HAVE BEEN IMPROVED AND CAN LEAD TO A STRONG SUPPRESSION OF VIRAL REPLICATION, IT IS DIFFICULT TO COMPLETELY ELIMINATE THE VIRUS WITH THESE THERAPIES ONCE CHRONIC HBV INFECTION IS ESTABLISHED IN THE HOST. FURTHERMORE, CHRONIC HBV INFECTION ALTERS INTRACELLULAR METABOLISM AND SIGNALLING PATHWAYS, RESULTING IN THE ACTIVATION OF CARCINOGENESIS IN THE LIVER. HBV PRODUCES FOUR VIRAL PROTEINS: HEPATITIS B SURFACE-, HEPATITIS B CORE-, HEPATITIS B X PROTEIN, AND POLYMERASE; EACH PLAYS AN IMPORTANT ROLE IN HBV REPLICATION AND THE INTRACELLULAR SIGNALLING PATHWAYS ASSOCIATED WITH HEPATOCARCINOGENESIS. IN VITRO AND IN VIVO EXPERIMENTAL MODELS FOR ANALYZING HBV INFECTION AND REPLICATION HAVE BEEN ESTABLISHED, AND GENE EXPRESSION ANALYSES USING MICROARRAYS OR NEXT-GENERATION SEQUENCING HAVE ALSO BEEN DEVELOPED. THUS, IT IS POSSIBLE TO CLARIFY THE MOLECULAR MECHANISMS FOR INTRACELLULAR ALTERATIONS, SUCH AS ENDOPLASMIC RETICULUM STRESS, OXIDATIVE STRESS, AND EPIGENETIC MODIFICATIONS. IN THIS REVIEW, THE IMPACT OF HBV VIRAL PROTEINS AND INTRACELLULAR ALTERATIONS IN HBV-ASSOCIATED HEPATOCARCINOGENESIS ARE DISCUSSED. 2021 4 6115 42 THE EPIGENETIC CONTROL OF HEPATITIS B VIRUS MODULATES THE OUTCOME OF INFECTION. EPIGENETIC MODIFICATIONS ARE STABLE ALTERATIONS IN GENE EXPRESSION THAT DO NOT INVOLVE MUTATIONS OF THE GENETIC SEQUENCE ITSELF. IT HAS BECOME INCREASINGLY CLEAR THAT EPIGENETIC FACTORS CONTRIBUTE TO THE OUTCOME OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION BY AFFECTING CELLULAR AND VIRION GENE EXPRESSION, VIRAL REPLICATION AND THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. HBV PERSISTS IN THE NUCLEUS OF INFECTED HEPATOCYTES AS A STABLE NON-INTEGRATED COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) WHICH FUNCTIONS AS A MINICHROMOSOME. THERE ARE TWO MAJOR FORMS OF HBV EPIGENETIC REGULATION: POSTTRANSLATIONAL MODIFICATION OF HISTONE PROTEINS ASSOCIATED WITH THE CCCDNA MINICHROMOSOME AND DNA METHYLATION OF VIRAL AND HOST GENOMES. THIS REVIEW EXPLORES HOW HBV CAN INTERPHASE WITH HOST EPIGENETIC REGULATION IN ORDER TO EVADE HOST DEFENCES AND TO PROMOTE ITS OWN SURVIVAL AND PERSISTENCE. WE FOCUS ON THE EFFECT OF CCCDNA BOUND-HISTONE MODIFICATIONS AND THE METHYLATION STATUS OF HBV DNA IN REGULATING VIRAL REPLICATION. INVESTIGATION OF HBV EPIGENETIC CONTROL HAS IMPORTANT CLINICAL CORRELATES WITH REGARDS TO THE DEVELOPMENT OF POTENTIAL THERAPEUTIC REGIMENS THAT WILL SUCCESSFULLY ERADICATE HBV INFECTION AND DEAL WITH HBV REACTIVATION IN THOSE UNDERGOING TREATMENT WITH DEMETHYLATING AGENTS. 2015 5 2240 45 EPIGENETIC MODULATION IN CHRONIC HEPATITIS B VIRUS INFECTION. THE HUMAN HEPATITIS B VIRUS (HBV) IS A SMALL-ENVELOPED DNA VIRUS CAUSING ACUTE AND CHRONIC HEPATITIS. DESPITE THE EXISTENCE OF AN EFFECTIVE PROPHYLACTIC VACCINE AND THE STRONG CAPACITY OF APPROVED ANTIVIRAL DRUGS TO SUPPRESS VIRAL REPLICATION, CHRONIC HBV INFECTION (CHB) CONTINUES TO BE A MAJOR HEALTH BURDEN WORLDWIDE. BOTH THE INABILITY OF THE IMMUNE SYSTEM TO RESOLVE CHB AND THE UNIQUE REPLICATION STRATEGY EMPLOYED BY HBV, WHICH FORMS A STABLE VIRAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) MINICHROMOSOME IN THE HEPATOCYTE NUCLEUS, ENABLE INFECTION PERSISTENCE. KNOWLEDGE OF THE COMPLEX NETWORK OF INTERACTIONS THAT HBV ENGAGES WITH ITS HOST IS STILL LIMITED BUT ACCUMULATING EVIDENCE INDICATES THAT EPIGENETIC MODIFICATIONS OCCURRING BOTH ON THE CCCDNA AND ON THE HOST GENOME IN THE COURSE OF INFECTION ARE ESSENTIAL TO MODULATE VIRAL ACTIVITY AND LIKELY CONTRIBUTE TO PATHOGENESIS AND CANCER DEVELOPMENT. THUS, A DEEPER UNDERSTANDING OF EPIGENETIC REGULATORY PROCESSES MAY OPEN NEW VENUES TO CONTROL AND EVENTUALLY CURE CHB. THIS REVIEW SUMMARIZES MAJOR FINDINGS IN HBV EPIGENETIC RESEARCH, FOCUSING ON THE EPIGENETIC MECHANISMS REGULATING CCCDNA ACTIVITY AND THE MODIFICATIONS DETERMINED IN INFECTED HOST CELLS AND TUMOR LIVER TISSUES. 2020 6 4055 44 MAPPING OF HISTONE MODIFICATIONS IN EPISOMAL HBV CCCDNA UNCOVERS AN UNUSUAL CHROMATIN ORGANIZATION AMENABLE TO EPIGENETIC MANIPULATION. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AFFECTS 240 MILLION PEOPLE WORLDWIDE AND IS A MAJOR RISK FACTOR FOR LIVER FAILURE AND HEPATOCELLULAR CARCINOMA. CURRENT ANTIVIRAL THERAPY INHIBITS CYTOPLASMIC HBV GENOMIC REPLICATION, BUT IS NOT CURATIVE BECAUSE IT DOES NOT DIRECTLY AFFECT NUCLEAR HBV CLOSED CIRCULAR DNA (CCCDNA), THE GENOMIC FORM THAT TEMPLATES VIRAL TRANSCRIPTION AND SUSTAINS VIRAL PERSISTENCE. NOVEL APPROACHES THAT DIRECTLY TARGET CCCDNA REGULATION WOULD THEREFORE BE HIGHLY DESIRABLE. CCCDNA IS ASSEMBLED WITH CELLULAR HISTONE PROTEINS INTO CHROMATIN, BUT LITTLE IS KNOWN ABOUT THE REGULATION OF HBV CHROMATIN BY HISTONE POSTTRANSLATIONAL MODIFICATIONS (PTMS). HERE, USING A NEW CCCDNA CHIP-SEQ APPROACH, WE REPORT, TO OUR KNOWLEDGE, THE FIRST GENOME-WIDE MAPS OF PTMS IN CCCDNA-CONTAINING CHROMATIN FROM DE NOVO INFECTED HEPG2 CELLS, PRIMARY HUMAN HEPATOCYTES, AND FROM HBV-INFECTED LIVER TISSUE. WE FIND HIGH LEVELS OF PTMS ASSOCIATED WITH ACTIVE TRANSCRIPTION ENRICHED AT SPECIFIC SITES WITHIN THE HBV GENOME AND, SURPRISINGLY, VERY LOW LEVELS OF PTMS LINKED TO TRANSCRIPTIONAL REPRESSION EVEN AT SILENT HBV PROMOTERS. WE SHOW THAT TRANSCRIPTION AND ACTIVE PTMS IN HBV CHROMATIN ARE REDUCED BY THE ACTIVATION OF AN INNATE IMMUNITY PATHWAY, AND THAT THIS EFFECT CAN BE RECAPITULATED WITH A SMALL MOLECULE EPIGENETIC MODIFYING AGENT, OPENING THE POSSIBILITY THAT CHROMATIN-BASED REGULATION OF CCCDNA TRANSCRIPTION COULD BE A NEW THERAPEUTIC APPROACH TO CHRONIC HBV INFECTION. 2015 7 4127 47 MECHANISMS OF DNA METHYLATION IN VIRUS-HOST INTERACTION IN HEPATITIS B INFECTION: PATHOGENESIS AND ONCOGENETIC PROPERTIES. HEPATITIS B VIRUS (HBV), THE WELL-STUDIED ONCOVIRUS THAT CONTRIBUTES TO THE MAJORITY OF HEPATOCELLULAR CARCINOMAS (HCC) WORLDWIDE, CAN CAUSE A SEVERE INFLAMMATORY MICROENVIRONMENT LEADING TO GENETIC AND EPIGENETIC CHANGES IN HEPATOCYTE CLONES. HBV REPLICATION CONTRIBUTES TO THE REGULATION OF DNA METHYLTRANSFERASE GENE EXPRESSION, PARTICULARLY BY X PROTEIN (HBX), AND SUBSEQUENT METHYLATION CHANGES MAY LEAD TO ABNORMAL TRANSCRIPTION ACTIVATION OF ADJACENT GENES AND GENOMIC INSTABILITY. UNDOUBTEDLY, THE ALTERED EXPRESSION OF THESE GENES HAS BEEN KNOWN TO CAUSE DIVERSE ASPECTS OF INFECTED HEPATOCYTES, INCLUDING APOPTOSIS, PROLIFERATION, REACTIVE OXYGEN SPECIES (ROS) ACCUMULATION, AND IMMUNE RESPONSES. ADDITIONALLY, POLLUTANT-INDUCED DNA METHYLATION CHANGES AND ABERRANT METHYLATION OF IMPRINTED GENES IN HEPATOCYTES ALSO COMPLICATE THE PROCESS OF TUMORIGENESIS. MEANWHILE, HEPATOCYTES ALSO CONTRIBUTE TO EPIGENETIC MODIFICATION OF THE VIRAL GENOME TO AFFECT HBV REPLICATION OR VIRAL PROTEIN PRODUCTION. MEANWHILE, METHYLATION LEVELS OF HBV INTEGRANTS AND SURROUNDING HOST REGIONS ALSO PLAY CRUCIAL ROLES IN THEIR ABILITY TO PRODUCE VIRAL PROTEINS IN AFFECTED HEPATOCYTES. BOTH HOST AND VIRAL CHANGES CAN PROVIDE NOVEL INSIGHTS INTO TUMORIGENESIS, INDIVIDUALIZED RESPONSES TO THERAPEUTIC INTERVENTION, DISEASE PROGRESS, AND EARLY DIAGNOSIS. AS SUCH, DNA METHYLATION-MEDIATED EPIGENETIC SILENCING OF CANCER-RELATED GENES AND VIRAL REPLICATION IS A COMPELLING THERAPEUTIC GOAL TO REDUCE MORBIDITY AND MORTALITY FROM LIVER CANCER CAUSED BY CHRONIC HBV INFECTION. IN THIS REVIEW, WE SUMMARIZE THE MOST RECENT RESEARCH ON ABERRANT DNA METHYLATION ASSOCIATED WITH HBV INFECTION, WHICH IS INVOLVED IN HCC DEVELOPMENT, AND PROVIDE AN OUTLOOK ON THE FUTURE DIRECTION OF THE RESEARCH. 2021 8 2324 37 EPIGENETIC REGULATION OF HEPATITIS B VIRUS COVALENTLY CLOSED CIRCULAR DNA: IMPLICATIONS FOR EPIGENETIC THERAPY AGAINST CHRONIC HEPATITIS B. HEPATITIS B VIRUS (HBV) INFECTION REPRESENTS A SIGNIFICANT PUBLIC HEALTH BURDEN WORLDWIDE. ALTHOUGH CURRENT THERAPEUTICS MANAGE TO CONTROL THE DISEASE PROGRESSION, LIFELONG TREATMENT AND SURVEILLANCE ARE REQUIRED BECAUSE DRUG RESISTANCE DEVELOPS DURING TREATMENT AND REACTIVATIONS FREQUENTLY OCCUR FOLLOWING MEDICATION CESSATION. THUS, THE OCCURRENCE OF HEPATOCELLULAR CARCINOMA IS DECREASED, BUT NOT ELIMINATED. ONE MAJOR REASON FOR FAILURE OF HBV TREATMENT IS THE INABILITY TO ERADICATE OR INACTIVATE THE VIRAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA), WHICH IS A STABLE EPISOMAL FORM OF THE VIRAL GENOME DECORATED WITH HOST HISTONES AND NONHISTONE PROTEINS. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC MODIFICATIONS OF CCCDNA CONTRIBUTE TO VIRAL REPLICATION AND THE OUTCOME OF CHRONIC HBV INFECTION. HERE, WE SUMMARIZE CURRENT PROGRESS ON HBV EPIGENETICS RESEARCH AND THE THERAPEUTIC IMPLICATIONS FOR CHRONIC HBV INFECTION BY LEARNING FROM THE EPIGENETIC THERAPIES FOR CANCER AND OTHER VIRAL DISEASES, WHICH MAY OPEN A NEW VENUE TO CURE CHRONIC HEPATITIS B. (HEPATOLOGY 2017;66:2066-2077). 2017 9 3782 43 INTERFERON THERAPY OF CHRONIC HEPATITIS B. CHRONIC HEPATITIS B (CHB) RESULTS FROM THE INABILITY OF THE HOST'S IMMUNE SYSTEM TO CONTROL VIRAL REPLICATION. INTERFERON-ALPHA (IFN-ALPHA) THERAPY CAN CONVERT CHB INTO INACTIVE HEPATITIS B VIRUS (HBV) INFECTION IN 20-30% OF THE TREATED PATIENTS. IN SPITE OF THE LOW RESPONSE RATE, IFN-ALPHA THERAPY HAS THE ADVANTAGE OF HAVING A LIMITED DURATION AND BEING EFFECTIVE EVEN AFTER THERAPY, AS DEMONSTRATED BY A MUCH HIGHER INCIDENCE OF HBSAG CLEARANCE IN RESPONDERS TO IFN-ALPHA THAN IN NATURALLY OCCURRING INACTIVE HBSAG CARRIERS. IFN-ALPHA HAS MULTIPLE ANTIVIRAL, ANTIPROLIFERATIVE, AND IMMUNOMODULATORY ACTIVITIES AND TARGETS: CELLULAR GENES (IFN-STIMULATED GENES) ACTIVATING DIFFERENT PATHWAYS OF ANTIVIRAL DEFENSE IN INFECTED AND NONINFECTED CELLS, HBV REPLICATION BLOCKING THE RNA-CONTAINING CORE PARTICLE FORMATION AND ACCELERATING THEIR DECAY, DEGRADING PREGENOMIC RNA, AND MODULATING THE NUCLEAR VIRAL MINICHROMOSOME (COVALENTLY CLOSED CIRCULAR DNA) ACTIVITY BY TARGETING ITS EPIGENETIC REGULATION AND BOTH INNATE AND ADAPTIVE IMMUNE RESPONSE. THE INTERFERENCE OF VIRAL HETEROGENEITY AND GENETIC POLYMORPHISMS OF THE HOST ON IFN-ALPHA SUSCEPTIBILITY IS UNDER INVESTIGATION. ONLY A BETTER UNDERSTANDING OF THE COMPLEX INTERPLAY BETWEEN THE DIFFERENT ACTIVITIES OF IFN-ALPHA WOULD WARRANT THE AMELIORATION OF CURRENT THERAPEUTIC STRATEGIES AND THE DESIGN OF NEW THERAPEUTIC APPROACHES. THE STUDY OF ON-TREATMENT DYNAMICS OF HBV INFECTION BY MEANS OF COMBINED QUANTITATIVE MONITORING OF SERUM HBV DNA AND HBSAG WARRANT TAILORING TREATMENT AT THE SINGLE-PATIENT LEVEL AND CAN HELP TO MAKE TREATMENT MORE COST-EFFECTIVE BY USING THE DIFFERENT COMBINATIONS OF CURRENTLY AVAILABLE ANTIVIRALS, INCLUDING IFN, MORE APPROPRIATELY. INTEGRATED MOLECULAR AND CLINICAL KNOWLEDGE IN A SYSTEMS MEDICINE FASHION IS MANDATORY TO FURTHER IMPROVE ANTIVIRAL THERAPY IN CHB. 2014 10 5368 30 RECENT ADVANCES IN THE STUDY OF HEPATITIS B VIRUS COVALENTLY CLOSED CIRCULAR DNA. CHRONIC HEPATITIS B INFECTION IS CAUSED BY HEPATITIS B VIRUS (HBV) AND A TOTAL CURE IS YET TO BE ACHIEVED. THE VIRAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IS THE KEY TO ESTABLISH A PERSISTENT INFECTION WITHIN HEPATOCYTES. CURRENT ANTIVIRAL STRATEGIES HAVE NO EFFECT ON THE PRE-EXISTING CCCDNA RESERVOIR. THEREFORE, THE STUDY OF THE MOLECULAR MECHANISM OF CCCDNA FORMATION IS BECOMING A MAJOR FOCUS OF HBV RESEARCH. THIS REVIEW SUMMARIZES THE CURRENT ADVANCES IN CCCDNA MOLECULAR BIOLOGY AND THE LATEST STUDIES ON THE ELIMINATION OR INACTIVATION OF CCCDNA, INCLUDING THREE MAJOR AREAS: (1) EPIGENETIC REGULATION OF CCCDNA BY HBV X PROTEIN, (2) IMMUNE-MEDIATED DEGRADATION, AND (3) GENOME-EDITING NUCLEASES. ALL THESE ASPECTS PROVIDE CLUES ON HOW TO FINALLY ATTAIN A CURE FOR CHRONIC HEPATITIS B INFECTION. 2017 11 2165 45 EPIGENETIC MECHANISMS IN HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. CHRONIC INFECTION OF THE LIVER BY THE HEPATITIS B VIRUS (HBV) IS ASSOCIATED WITH INCREASED RISK FOR DEVELOPING HEPATOCELLULAR CARCINOMA (HCC). A MULTITUDE OF STUDIES HAVE INVESTIGATED THE MECHANISM OF LIVER CANCER PATHOGENESIS DUE TO CHRONIC HBV INFECTION. CHRONIC INFLAMMATION, EXPRESSION OF SPECIFIC VIRAL PROTEINS SUCH AS HBX, THE INTEGRATION SITE OF THE VIRAL GENOME INTO THE HOST GENOME, AND THE VIRAL GENOTYPE, ARE KEY PLAYERS CONTRIBUTING TO HCC PATHOGENESIS. IN ADDITION, THE GENETIC BACKGROUND OF THE HOST AND EXPOSURE TO ENVIRONMENTAL CARCINOGENS ARE ALSO PREDISPOSING PARAMETERS IN HEPATOCARCINOGENESIS. DESPITE THE PLETHORA OF STUDIES, THE MOLECULAR MECHANISM OF HCC PATHOGENESIS REMAINS INCOMPLETELY UNDERSTOOD. IN THIS REVIEW, THE FOCUS IS ON EPIGENETIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF HBV-ASSOCIATED HCC. EPIGENETIC MECHANISMS ARE DYNAMIC MOLECULAR PROCESSES THAT REGULATE GENE EXPRESSION WITHOUT ALTERING THE HOST DNA, ACTING BY MODIFYING THE HOST CHROMATIN STRUCTURE VIA COVALENT POST-TRANSLATIONAL HISTONE MODIFICATIONS, CHANGING THE DNA METHYLATION STATUS, EXPRESSION OF NON-CODING RNAS SUCH AS MICRORNAS AND LONG NONCODING RNAS, AND ALTERING THE SPATIAL, 3-D ORGANIZATION OF THE CHROMATIN OF THE VIRUS-INFECTED CELL. HEREIN, STUDIES ARE DESCRIBED THAT PROVIDE EVIDENCE IN SUPPORT OF DEREGULATION OF EPIGENETIC MECHANISMS IN THE HBV-INFECTED/-REPLICATING HEPATOCYTE AND THEIR CONTRIBUTION TO HEPATOCYTE TRANSFORMATION. IN CONTRAST TO GENETIC MUTATIONS WHICH ARE PERMANENT, EPIGENETIC ALTERATIONS ARE DYNAMIC AND REVERSIBLE. ACCORDINGLY, THE IDENTIFICATION OF ESSENTIAL MOLECULAR EPIGENETIC TARGETS INVOLVED IN HBV-MEDIATED HCC PATHOGENESIS OFFERS THE OPPORTUNITY FOR THE DESIGN AND DEVELOPMENT OF NOVEL EPIGENETIC THERAPEUTIC APPROACHES. 2021 12 3255 43 HEPATITIS B VIRUS X PROTEIN MEDIATED EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF HEPATOCELLULAR CARCINOMA. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A WORLDWIDE HEALTH PROBLEM. HEPATITIS B VIRUS X PROTEIN (HBX), A PLEIOTROPIC REGULATORY PROTEIN ENCODED BY HBV, IS NECESSARY FOR THE TRANSCRIPTION OF HBV COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) MINICHROMOSOMES, AND AFFECTS THE EPIGENETIC REGULATION OF HOST CELLS. THE EPIGENETIC REPROGRAMMING OF HBX ON HOST CELL GENOME IS STRONGLY INVOLVED IN HBV-RELATED HCC CARCINOGENESIS. HERE, WE REVIEW THE LATEST FINDINGS OF THE EPIGENETIC REGULATION INDUCED BY HBX PROTEIN IN HEPATOCELLULAR CARCINOMA (HCC), INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNA EXPRESSION. THE INFLUENCE OF HBX ON THE EPIGENETIC REGULATION OF CCCDNA IS ALSO SUMMARIZED. IN ADDITION, PRELIMINARY STUDIES OF TARGETED DRUGS FOR EPIGENETIC CHANGES INDUCED BY HBX ARE ALSO DISCUSSED. THE EXPLORATION OF EPIGENETIC MARKERS AS POTENTIAL TARGETS WILL HELP TO DEVELOP NEW PREVENTION AND/OR TREATMENT METHODS FOR HBX-RELATED HCC. 2022 13 1178 36 CONTROL OF CCCDNA FUNCTION IN HEPATITIS B VIRUS INFECTION. THE TEMPLATE OF HEPATITIS B VIRUS (HBV) TRANSCRIPTION, THE COVALENTLY CLOSED CIRCULAR DNA (CCCDNA), PLAYS A KEY ROLE IN THE LIFE CYCLE OF THE VIRUS AND PERMITS THE PERSISTENCE OF INFECTION. NOVEL MOLECULAR TECHNIQUES HAVE OPENED NEW POSSIBILITIES TO INVESTIGATE THE ORGANIZATION AND THE ACTIVITY OF THE CCCDNA MINICHROMOSOME IN VIVO, AND RECENT ADVANCES HAVE STARTED TO SHED LIGHT ON THE COMPLEXITY OF THE MECHANISMS CONTROLLING CCCDNA FUNCTION. NUCLEAR CCCDNA ACCUMULATES IN HEPATOCYTE NUCLEI AS A STABLE MINICHROMOSOME ORGANIZED BY HISTONE AND NON-HISTONE VIRAL AND CELLULAR PROTEINS. IDENTIFICATION OF THE MOLECULAR MECHANISMS REGULATING CCCDNA STABILITY AND ITS TRANSCRIPTIONAL ACTIVITY AT THE RNA, DNA AND EPIGENETIC LEVELS IN THE COURSE OF CHRONIC HEPATITIS B (CH-B) INFECTION MAY REVEAL NEW POTENTIAL THERAPEUTIC TARGETS FOR ANTI-HBV DRUGS AND HENCE ASSIST IN THE DESIGN OF STRATEGIES AIMED AT SILENCING AND EVENTUALLY DEPLETING THE CCCDNA RESERVOIR. 2009 14 3401 30 HOW DID HEPATITIS B VIRUS EFFECT THE HOST GENOME IN THE LAST DECADE? THE PRINCIPAL REASON OF CHRONIC LIVER DISEASE, CIRRHOSIS AND HEPATOCELLULAR CARCINOMA IS CHRONIC VIRAL HEPATITIS ALL OVER THE WORLD. HEPATITIS B VIRUS (HBV) HAS SOME MUTAGENIC EFFECTS ON THE HOST GENOME. HBV MAY BE EXHIBITING THESE MUTAGENIC EFFECTS THROUGH INTEGRATING INTO THE HOST GENOME, THROUGH ITS VIRAL PROTEINS OR THROUGH SOME EPIGENETIC MECHANISMS RELATED WITH HBV PROTEINS. THIS REVIEW AIMS TO SUMMARIZE THE MOLECULAR MECHANISMS USED BY HBV FOR EFFECTING HOST GENOME DETERMINED IN THE LAST DECADE. THE FOCUS WILL BE ON THE EFFECTS OF INTEGRATION, HBV PROTEINS, ESPECIALLY HBV X PROTEIN AND EPIGENETIC MECHANISMS ON THE HOST GENOME. THESE INTERACTIONS BETWEEN HBV AND THE HOST GENOME ALSO FORMS THE UNDERLYING MECHANISMS OF THE EVOLUTION OF HEPATOCELLULAR CARCINOMA. 2014 15 5936 32 TARGETING HEPATITIS B VIRUS COVALENTLY CLOSED CIRCULAR DNA AND HEPATITIS B VIRUS X PROTEIN: RECENT ADVANCES AND NEW APPROACHES. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION REMAINS A WORLDWIDE CONCERN AND PUBLIC HEALTH PROBLEM. TWO KEY ASPECTS OF THE HBV LIFE CYCLE ARE ESSENTIAL FOR VIRAL REPLICATION AND THUS THE DEVELOPMENT OF CHRONIC INFECTIONS: THE ESTABLISHMENT OF THE VIRAL MINICHROMOSOME, COVALENTLY CLOSED CIRCULAR (CCC) DNA, WITHIN THE NUCLEUS OF INFECTED HEPATOCYTES AND THE EXPRESSION OF THE REGULATORY HEPATITIS B VIRUS X PROTEIN (HBX). INTERESTINGLY, NUCLEAR HBX REDIRECTS HOST EPIGENETIC MACHINERY TO ACTIVATE CCCDNA TRANSCRIPTION. IN THIS PERSPECTIVE, WE PROVIDE AN OVERVIEW OF RECENT ADVANCES IN UNDERSTANDING THE REGULATION OF CCCDNA AND THE MECHANISTIC AND FUNCTIONAL ROLES OF HBX. WE ALSO DESCRIBE THE PROGRESS TOWARD TARGETING BOTH CCCDNA AND HBX FOR THERAPEUTIC PURPOSES. FINALLY, WE OUTLINE STANDING QUESTIONS IN THE FIELD AND PROPOSE COMPLEMENTARY CHEMICAL BIOLOGY APPROACHES TO ADDRESS THEM. 2019 16 2939 29 GENETIC AND EPIGENETIC ALTERATIONS IN HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. HEPATITIS B VIRUS (HBV) IS A MAJOR CAUSE OF HEPATOCELLULAR CARCINOMA (HCC). ITS CHRONIC INFECTION CAN LEAD TO CHRONIC LIVER INFLAMMATION AND THE ACCUMULATION OF GENETIC ALTERATIONS TO RESULT IN THE ONCOGENIC TRANSFORMATION OF HEPATOCYTES. HBV CAN ALSO SENSITIZE HEPATOCYTES TO ONCOGENIC TRANSFORMATION BY CAUSING GENETIC AND EPIGENETIC CHANGES OF THE HOST CHROMOSOMES. HBV DNA CAN INSERT INTO HOST CHROMOSOMES AND RECENT LARGE-SCALE WHOLE-GENOME SEQUENCING STUDIES REVEALED RECURRENT HBV DNA INTEGRATIONS SITES THAT MAY PLAY IMPORTANT ROLES IN THE INITIATION OF HEPATOCELLULAR CARCINOGENESIS. HBV CAN ALSO CAUSE EPIGENETIC CHANGES BY ALTERING THE METHYLATION STATUS OF CELLULAR DNA, THE POST-TRANSLATIONAL MODIFICATION OF HISTONES, AND THE EXPRESSION OF MICRORNAS. THESE CHANGES CAN ALSO LEAD TO THE EVENTUAL HEPATOCELLULAR TRANSFORMATION. THESE RECENT FINDINGS ON THE GENETIC AND EPIGENETIC ALTERATIONS OF THE HOST CHROMOSOMES INDUCED BY HBV OPENED A NEW AVENUE FOR THE DEVELOPMENT OF NOVEL DIAGNOSIS AND TREATMENTS FOR HBV-INDUCED HCC. 2015 17 3806 45 INTRACELLULAR INTERFERON SIGNALLING PATHWAYS AS POTENTIAL REGULATORS OF COVALENTLY CLOSED CIRCULAR DNA IN THE TREATMENT OF CHRONIC HEPATITIS B. INFECTION WITH THE HEPATITIS B VIRUS (HBV) IS STILL A MAJOR GLOBAL HEALTH THREAT AS 250 MILLION PEOPLE WORLDWIDE CONTINUE TO BE CHRONICALLY INFECTED WITH THE VIRUS. WHILE PATIENTS MAY BE TREATED WITH NUCLEOSIDE/NUCLEOTIDE ANALOGUES, THIS ONLY SUPPRESSES HBV TITRE TO SUB-DETECTION LEVELS WITHOUT ELIMINATING THE PERSISTENT HBV COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) GENOME. AS A RESULT, HBV INFECTION CANNOT BE CURED, AND THE VIRUS REACTIVATES WHEN CONDITIONS ARE FAVORABLE. INTERFERONS (IFNS) ARE CYTOKINES KNOWN TO INDUCE POWERFUL ANTIVIRAL MECHANISMS THAT CLEAR VIRUSES FROM INFECTED CELLS. THEY HAVE BEEN SHOWN TO INDUCE CCCDNA CLEARANCE, BUT THEIR USE IN THE TREATMENT OF HBV INFECTION IS LIMITED AS HBV-TARGETING IMMUNE CELLS ARE EXHAUSTED AND HBV HAS EVOLVED MULTIPLE MECHANISMS TO EVADE AND SUPPRESS IFN SIGNALLING. THUS, TO FULLY UTILIZE IFN-MEDIATED INTRACELLULAR MECHANISMS TO EFFECTIVELY ELIMINATE HBV, INSTEAD OF DIRECT IFN ADMINISTRATION, NOVEL STRATEGIES TO SUSTAIN IFN-MEDIATED ANTI-CCCDNA AND ANTIVIRAL MECHANISMS NEED TO BE DEVELOPED. THIS REVIEW WILL CONSOLIDATE WHAT IS KNOWN ABOUT HOW IFNS ACT TO ACHIEVE ITS INTRACELLULAR ANTIVIRAL EFFECTS AND HIGHLIGHT THE CRITICAL INTERFERON-STIMULATED GENE TARGETS AND EFFECTOR MECHANISMS WITH POTENT ANTI-CCCDNA FUNCTIONS. THESE INCLUDE CCCDNA DEGRADATION BY APOBECS AND CCCDNA SILENCING AND TRANSCRIPTION REPRESSION BY EPIGENETIC MODIFICATIONS. IN ADDITION, THE MECHANISMS THAT HBV EMPLOYS TO DISRUPT IFN SIGNALLING WILL BE DISCUSSED. DRUGS THAT HAVE BEEN DEVELOPED OR ARE IN THE PIPELINE FOR COMPONENTS OF THE IFN SIGNALLING PATHWAY AND HBV TARGETS THAT DETRACT IFN SIGNALLING MECHANISMS WILL ALSO BE IDENTIFIED AND DISCUSSED FOR UTILITY IN THE TREATMENT OF HBV INFECTIONS. TOGETHER, THESE WILL PROVIDE USEFUL INSIGHTS INTO DESIGN STRATEGIES THAT SPECIFICALLY TARGET CCCDNA FOR THE ERADICATION OF HBV. 2021 18 3187 40 HBV INDUCED HEPATOCELLULAR CARCINOMA AND RELATED POTENTIAL IMMUNOTHERAPY. CHRONIC INFECTION OF HEPATITIS B VIRUS (HBV) HAS LONG BEEN RECOGNIZED AS A MAJOR RISK FACTOR IN THE INITIATION AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), CONTRIBUTING TO OVER HALF THE CASES OF HCC WORLDWIDE. TRANSFORMATION OF THE LIVER WITH HBV INFECTION TO HCC MAINLY RESULTS FROM LONG-TERM INTERACTION BETWEEN HBV AND THE HOST HEPATOCYTES VIA A VARIETY OF MECHANISMS, INCLUDING HBV DNA INTEGRATION, PROLONGED EXPRESSION OF THE VIRAL HBX REGULATORY PROTEIN AND/OR ABERRANT PRES/S ENVELOPE PROTEINS, AND EPIGENETIC DYSREGULATION OF TUMOR SUPPRESSOR GENES. WHILE THERE HAVE BEEN SEVERAL FAILURES IN THE DEVELOPMENT OF DRUGS FOR HCC, THE IMMUNE-TOLERANT MICROENVIRONMENT OF THIS MALIGNANCY SUGGESTS THAT IMMUNOTHERAPEUTIC AGENTS COULD PROVIDE BENEFITS FOR THESE PATIENTS. THIS IS SUPPORTED BY RECENT DATA SHOWING THAT IMMUNOTHERAPY HAS PROMISING ACTIVITY IN PATIENTS WITH ADVANCED HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF HBV-INDUCED HCC AND RECENT IMMUNE BASED APPROACHES FOR THE TREATMENT OF HCC PATIENTS. 2020 19 6271 37 THE ONCOGENIC ROLE OF HEPATITIS B VIRUS. THE HEPATITIS B VIRUS (HBV) IS A SMALL ENVELOPED DNA VIRUS THAT CAUSES ACUTE AND CHRONIC HEPATITIS. HBV INFECTION IS A WORLD HEALTH PROBLEM, WITH 350 MILLION CHRONICALLY INFECTED PEOPLE AT INCREASED RISK OF DEVELOPING LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC). HBV HAS BEEN CLASSIFIED AMONG HUMAN TUMOR VIRUSES BY VIRTUE OF A ROBUST EPIDEMIOLOGIC ASSOCIATION BETWEEN CHRONIC HBV CARRIAGE AND HCC OCCURRENCE. IN THE ABSENCE OF CYTOPATHIC EFFECT IN INFECTED HEPATOCYTES, THE ONCOGENIC ROLE OF HBV MIGHT INVOLVE A COMBINATION OF DIRECT AND INDIRECT EFFECTS OF THE VIRUS DURING THE MULTISTEP PROCESS OF LIVER CARCINOGENESIS. LIVER INFLAMMATION AND HEPATOCYTE PROLIFERATION DRIVEN BY HOST IMMUNE RESPONSES ARE RECOGNIZED DRIVING FORCES OF LIVER CELL TRANSFORMATION. GENETIC AND EPIGENETIC ALTERATIONS CAN ALSO RESULT FROM VIRAL DNA INTEGRATION INTO HOST CHROMOSOMES AND FROM PROLONGED EXPRESSION OF VIRAL GENE PRODUCTS. NOTABLY, THE TRANSCRIPTIONAL REGULATORY PROTEIN HBX ENCODED BY THE X GENE IS ENDOWED WITH TUMOR PROMOTER ACTIVITY. HBX HAS PLEIOTROPIC ACTIVITIES AND PLAYS A MAJOR ROLE IN HBV PATHOGENESIS AND IN LIVER CARCINOGENESIS. BECAUSE HEPATIC TUMORS CARRY A DISMAL PROGNOSIS, THERE IS URGENT NEED TO DEVELOP EARLY DIAGNOSTIC MARKERS OF HCC AND EFFECTIVE THERAPIES AGAINST CHRONIC HEPATITIS B. DECIPHERING THE ONCOGENIC MECHANISMS THAT UNDERLIE HBV-RELATED TUMORIGENESIS MIGHT HELP DEVELOPING ADAPTED THERAPEUTIC STRATEGIES. 2014 20 4920 33 PARALLEL EPIGENETIC AND GENETIC CHANGES IN THE PATHOGENESIS OF HEPATITIS VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST FREQUENT TUMOR TYPES IN THE WORLD, WITH SHORT SURVIVAL TIMES AND FEW TREATMENT OPTIONS. HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) ARE MAJOR ETIOLOGIC AGENTS OF HCC, ALTHOUGH THE ASSOCIATED MECHANISMS ARE INCOMPLETELY UNDERSTOOD. THE AVAILABLE EVIDENCE SUGGESTS THAT BOTH VIRUSES PROMOTE TUMORIGENESIS BY UP-REGULATING GENES THAT PROMOTE HEPATOCELLULAR GROWTH AND SURVIVAL, AND BY DOWN-REGULATING OTHER GENES THAT ACT AS TUMOR SUPPRESSORS AND NEGATIVE GROWTH REGULATORY MOLECULES. SIGNIFICANTLY, A NUMBER OF THE PATHWAYS THAT ARE ALTERED BY THESE VIRUSES ARE THE SAME ONES THAT ACCUMULATE GENETIC ALTERATIONS DURING TUMOR PROGRESSION. THIS SUGGESTS THAT THE PATHWAYS THAT PROMOTE VIRUS PERSISTENCE AND REPLICATION MAY ALSO PROMOTE CELL GROWTH AND SURVIVAL. FROM THE PERSPECTIVE OF THE VIRUS, THIS PROMOTES CHRONIC INFECTION, WHILE FROM THE PERSPECTIVE OF THE HOST, THIS PROMOTES TUMORIGENESIS. 2006