1 4817 126 OCCULT HEPATITIS B VIRUS INFECTION: AN UPDATE. OCCULT HEPATITIS B VIRUS (HBV) INFECTION (OBI) REFERS TO A CONDITION IN WHICH REPLICATION-COMPETENT VIRAL DNA IS PRESENT IN THE LIVER (WITH DETECTABLE OR UNDETECTABLE HBV DNA IN THE SERUM) OF INDIVIDUALS TESTING NEGATIVE FOR THE HBV SURFACE ANTIGEN (HBSAG). IN THIS PECULIAR PHASE OF HBV INFECTION, THE COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IS IN A LOW STATE OF REPLICATION. MANY ADVANCES HAVE BEEN MADE IN CLARIFYING THE MECHANISMS INVOLVED IN SUCH A SUPPRESSION OF VIRAL ACTIVITY, WHICH SEEMS TO BE MAINLY RELATED TO THE HOST'S IMMUNE CONTROL AND EPIGENETIC FACTORS. OBI IS DIFFUSED WORLDWIDE, BUT ITS PREVALENCE IS HIGHLY VARIABLE AMONG PATIENT POPULATIONS. THIS DEPENDS ON DIFFERENT GEOGRAPHIC AREAS, RISK FACTORS FOR PARENTERAL INFECTIONS, AND ASSAYS USED FOR HBSAG AND HBV DNA DETECTION. OBI HAS AN IMPACT IN SEVERAL CLINICAL CONTEXTS: (A) IT CAN BE TRANSMITTED, CAUSING A CLASSIC FORM OF HEPATITIS B, THROUGH BLOOD TRANSFUSION OR LIVER TRANSPLANTATION; (B) IT MAY REACTIVATE IN THE CASE OF IMMUNOSUPPRESSION, LEADING TO THE POSSIBLE DEVELOPMENT OF EVEN FULMINANT HEPATITIS; (C) IT MAY ACCELERATE THE PROGRESSION OF CHRONIC LIVER DISEASE DUE TO DIFFERENT CAUSES TOWARD CIRRHOSIS; (D) IT MAINTAINS THE PRO-ONCOGENIC PROPERTIES OF THE "OVERT" INFECTION, FAVORING THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. 2022 2 4816 58 OCCULT HEPATITIS B VIRUS INFECTION: A COMPLEX ENTITY WITH RELEVANT CLINICAL IMPLICATIONS. OCCULT HEPATITIS B VIRUS (HBV) INFECTION IS A WORLD-WIDE ENTITY, FOLLOWING THE GEOGRAPHICAL DISTRIBUTION OF DETECTABLE HEPATITIS B. THIS ENTITY IS DEFINED AS THE PERSISTENCE OF VIRAL GENOMES IN THE LIVER TISSUE AND IN SOME INSTANCES ALSO IN THE SERUM, ASSOCIATED TO NEGATIVE HBV SURFACE ANTIGEN SEROLOGY. THE MOLECULAR BASIS OF THE OCCULT INFECTION IS RELATED TO THE LIFE CYCLE OF HBV, WHICH PRODUCES A COVALENTLY CLOSED CIRCULAR DNA THAT PERSISTS IN THE CELL NUCLEI AS AN EPISOME, AND SERVES AS A TEMPLATE FOR GENE TRANSCRIPTION. THE MECHANISM RESPONSIBLE FOR THE HBSAG NEGATIVE STATUS IN OCCULT HBV CARRIERS IS A STRONG SUPPRESSION OF VIRAL REPLICATION, PROBABLY DUE TO THE HOST'S IMMUNE RESPONSE, CO-INFECTION WITH OTHER INFECTIOUS AGENTS AND EPIGENETIC FACTORS. THERE IS EMERGING EVIDENCE OF THE POTENTIAL CLINICAL RELEVANCE OF OCCULT HBV INFECTION, SINCE THIS COULD BE INVOLVED IN OCCULT HBV TRANSMISSION THROUGH ORTHOTOPIC LIVER TRANSPLANT AND BLOOD TRANSFUSION, REACTIVATION OF HBV INFECTION DURING IMMUNOSUPPRESSION, IMPAIRING CHRONIC LIVER DISEASE OUTCOME AND ACTING AS A RISK FACTOR FOR HEPATOCELLULAR CARCINOMA. THEREFORE IT IS IMPORTANT TO BEAR IN MIND THIS ENTITY IN CRYPTOGENETIC LIVER DISEASES, HEPATITIS C VIRUS/HIV INFECTED PATIENTS AND IMMUNOSUPRESSED INDIVIDUALS. IT IS ALSO NECESSARY TO INCREASE OUR KNOWLEDGE IN THIS FASCINATING FIELD TO DEFINE BETTER STRATEGIES TO DIAGNOSE AND TREAT THIS INFECTION. 2011 3 1397 25 DIET PHYTOCHEMICALS AND CUTANEOUS CARCINOMA CHEMOPREVENTION: A REVIEW. CUTANEOUS CARCINOMA, WHICH HAS OCCUPIED A PECULIAR PLACE AMONG WORLDWIDE POPULATIONS, IS COMMONLY RESPONSIBLE FOR THE CONSIDERABLY INCREASING MORBIDITY AND MORTALITY RATES. CURRENTLY AVAILABLE MEDICAL PROCEDURES FAIL TO COMPLETELY AVOID CUTANEOUS CARCINOMA DEVELOPMENT OR TO PREVENT MORTALITY. CANCER CHEMOPREVENTION, AS AN ALTERNATIVE STRATEGY, IS BEING CONSIDERED TO REDUCE THE INCIDENCE AND BURDEN OF CANCERS THROUGH CHEMICAL AGENTS. DERIVED FROM DIETARY FOODS, PHYTOCHEMICALS HAVE BECOME SAFE AND RELIABLE COMPOUNDS FOR THE CHEMOPREVENTION OF CUTANEOUS CARCINOMA BY RELIEVING MULTIPLE PATHOLOGICAL PROCESSES, INCLUDING OXIDATIVE DAMAGE, EPIGENETIC ALTERATION, CHRONIC INFLAMMATION, ANGIOGENESIS, ETC. IN THIS REVIEW, WE PRESENTED COMPREHENSIVE KNOWLEDGES, MAIN MOLECULAR MECHANISMS FOR THE INITIATION AND DEVELOPMENT OF CUTANEOUS CARCINOMA AS WELL AS EFFECTS OF VARIOUS DIET PHYTOCHEMICALS ON CHEMOPREVENTION. 2017 4 4815 64 OCCULT HEPATITIS B INFECTION AND HEPATOCELLULAR CARCINOMA: EPIDEMIOLOGY, VIROLOGY, HEPATOCARCINOGENESIS AND CLINICAL SIGNIFICANCE. OCCULT HEPATITIS B INFECTION (OBI) REFERS TO A CONDITION WHERE REPLICATION-COMPETENT HBV DNA IS PRESENT IN THE LIVER, WITH OR WITHOUT HBV DNA IN THE BLOOD, IN INDIVIDUALS WITH SERUM HBSAG NEGATIVITY ASSESSED BY CURRENTLY AVAILABLE ASSAYS. THE EPISOMAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IN OBI IS IN A LOW REPLICATIVE STATE. VIRAL GENE EXPRESSION IS MEDIATED BY EPIGENETIC CONTROL OF HBV TRANSCRIPTION, INCLUDING THE HBV CPG ISLAND METHYLATION PATHWAY AND POST-TRANSLATIONAL MODIFICATION OF CCCDNA-BOUND HISTONE, WITH A DIFFERENT PATTERN FROM PATIENTS WITH CHRONIC HBV INFECTION. THE PREVALENCE OF OBI VARIES TREMENDOUSLY ACROSS PATIENT POPULATIONS OWING TO NUMEROUS FACTORS, SUCH AS GEOGRAPHIC LOCATION, ASSAY CHARACTERISTICS, HOST IMMUNE RESPONSE, COINFECTION WITH OTHER VIRUSES, AND VACCINATION STATUS. APART FROM THE RISK OF VIRAL REACTIVATION UPON IMMUNOSUPPRESSION AND THE RISK OF TRANSMISSION OF HBV, OBI HAS BEEN IMPLICATED IN HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT IN PATIENTS WITH CHRONIC HCV INFECTION, THOSE WITH CRYPTOGENIC OR KNOWN LIVER DISEASE, AND IN PATIENTS WITH HBSAG SEROCLEARANCE AFTER CHRONIC HBV INFECTION. AN INCREASING NUMBER OF PROSPECTIVE STUDIES AND META-ANALYSES HAVE REPORTED A HIGHER INCIDENCE OF HCC IN PATIENTS WITH HCV AND OBI, AS WELL AS MORE ADVANCED TUMOUR HISTOLOGICAL GRADES AND EARLIER AGE OF HCC DIAGNOSIS, COMPARED WITH PATIENTS WITHOUT OBI. THE PROPOSED PATHOGENETIC MECHANISMS OF OBI-RELATED HCC INCLUDE THE INFLUENCE OF HBV DNA INTEGRATION ON THE HEPATOCYTE CELL CYCLE, THE PRODUCTION OF PRO-ONCOGENIC PROTEINS (HBX PROTEIN AND MUTATED SURFACE PROTEINS), AND PERSISTENT LOW-GRADE NECROINFLAMMATION (CONTRIBUTING TO THE DEVELOPMENT OF FIBROSIS AND CIRRHOSIS). THERE REMAIN UNCERTAINTIES ABOUT EXACTLY HOW, AND IN WHAT ORDER, THESE MECHANISMS DRIVE THE DEVELOPMENT OF TUMOURS IN PATIENTS WITH OBI. 2020 5 6862 57 [OCCULT HEPATITIS B VIRUS INFECTION]. OCCULT HEPATITIS B VIRUS (HBV) INFECTION IS A PECULIAR FORM OF CHRONIC VIRAL INFECTION IDENTIFIED SINCE THE EARLY 80'S AND CAN BE DEFINED AS THE PRESENCE OF HBV DNA IN THE SERUM AND/OR IN THE LIVER TISSUE OF PATIENTS NEGATIVE FOR THE HBV SURFACE ANTIGEN (HBSAG) USING USUAL SEROLOGICAL TESTS. THE DATA ABOUT THE PREVALENCE OF OCCULT HBV INFECTION ARE CONTRASTING AND THE REPORTED PREVALENCES IN VARIOUS CATEGORIES OF INDIVIDUALS ARE HIGHLY DIVERSE. THE MOLECULAR BASIS OF THE OCCULT HBV INFECTION IS THE COVALENTLY CLOSED-CIRCULAR DNA (CCCDNA) THAT PERSISTS IN THE CELL NUCLEI AND THAT SERVES AS A TEMPLATE FOR GENE TRANSCRIPTION. THE PHYSIOPATHOLOGY OF OCCULT HBV INFECTION IS STILL UNCLEAR. HOWEVER, THE AVAILABLE DATA SUGGEST THAT THE HOST'S IMMUNE RESPONSE, THE CO-INFECTIONS WITH OTHER INFECTIOUS AGENTS AND EPIGENETIC FACTORS MAY PLAY IMPORTANT ROLES IN INDICING THE OCCULT STATUS. THE CLINICAL RELEVANCE OF OCCULTHBVINFECTION REMAINS DEBATED BUT IT MAY IMPACT IN FOUR CLINICAL CONTEXTS: 1) THE TRANSMISSION OF THE INFECTION BY BLOOD TRANSFUSION OR ORGAN TRANSPLANTATION; 2) THE ACUTE REACTIVATION WHEN AN IMMUNOSUPPRESSIVE STATUS OCCURS MAINLY IN PATIENTS WITH ISOLATED ANTI-HBC (CHEMOTHERAPY, TRANSPLANTATIONS, IMMUNODEPRESSION, NEW IMMUNOSUPPRESSIVE THERAPY AS ANTI-CD20 OR ANTI TNF); 3) THE POTENT BUT NON PROVED PROGRESSION OF LIVER FIBROSIS IN HCV INFECTED PATIENTS OR IN PATIENTS WITH CRYPTOGENETIC LIVER DISEASE; AND, 4. THE RISK FACTOR FOR HEPATOCELLULAR CARCINOMA DEVELOPMENT. 2008 6 6641 29 UNRAVELING THE MULTIFACETED NATURE OF CD8 T CELL EXHAUSTION PROVIDES THE MOLECULAR BASIS FOR THERAPEUTIC T CELL RECONSTITUTION IN CHRONIC HEPATITIS B AND C. IN CHRONIC HEPATITIS B AND C VIRUS INFECTIONS PERSISTENTLY ELEVATED ANTIGEN LEVELS DRIVE CD8+ T CELLS TOWARD A PECULIAR DIFFERENTIATION STATE KNOWN AS T CELL EXHAUSTION, WHICH POSES CRUCIAL CONSTRAINTS TO ANTIVIRAL IMMUNITY. AVAILABLE EVIDENCE INDICATES THAT T CELL EXHAUSTION IS ASSOCIATED WITH A SERIES OF METABOLIC AND SIGNALING DEREGULATIONS AND WITH A VERY PECULIAR EPIGENETIC STATUS WHICH ALL TOGETHER LEAD TO REDUCED EFFECTOR FUNCTIONS. A CLEAR MECHANISTIC NETWORK EXPLAINING HOW INTRACELLULAR METABOLIC DERANGEMENTS, TRANSCRIPTIONAL AND SIGNALING ALTERATIONS SO FAR DESCRIBED ARE INTERCONNECTED IN A COMPREHENSIVE AND UNIFIED VIEW OF THE T CELL EXHAUSTION DIFFERENTIATION PROFILE IS STILL LACKING. ADDRESSING THIS ISSUE IS OF KEY IMPORTANCE FOR THE DEVELOPMENT OF INNOVATIVE STRATEGIES TO BOOST HOST IMMUNITY IN ORDER TO ACHIEVE VIRAL CLEARANCE. THIS REVIEW WILL DISCUSS THE CURRENT KNOWLEDGE IN HBV AND HCV INFECTIONS, ADDRESSING HOW INNATE IMMUNITY, METABOLIC DERANGEMENTS, EXTENSIVE STRESS RESPONSES AND ALTERED EPIGENETIC PROGRAMS MAY BE TARGETED TO RESTORE FUNCTIONALITY AND RESPONSIVENESS OF VIRUS-SPECIFIC CD8 T CELLS IN THE CONTEXT OF CHRONIC VIRUS INFECTIONS. 2021 7 5952 46 TARGETING VIRAL CCCDNA FOR CURE OF CHRONIC HEPATITIS B. PURPOSE OF REVIEW: CHRONIC HEPATITIS B (CHB), CAUSED BY HEPATITIS B VIRUS (HBV), IS A MAJOR CAUSE OF ADVANCED LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC) WORLDWIDE. HBV REPLICATION IS CHARACTERIZED BY THE SYNTHESIS OF COVALENTLY CLOSED CIRCULAR (CCC) DNA WHICH IS NOT TARGETED BY ANTIVIRAL NUCLEOS(T)IDE ANALOGUES (NUCS) THE KEY MODALITY OF STANDARD OF CARE. WHILE HBV REPLICATION IS SUCCESSFULLY SUPPRESSED IN TREATED PATIENTS, THEY REMAIN AT RISK FOR DEVELOPING HCC. WHILE FUNCTIONAL CURE, CHARACTERIZED BY LOSS OF HBSAG, IS THE FIRST GOAL OF NOVEL ANTIVIRAL THERAPIES, CURATIVE TREATMENTS ELIMINATING CCCDNA REMAIN THE ULTIMATE GOAL. THIS REVIEW SUMMARIZES RECENT ADVANCES IN THE DISCOVERY AND DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES AND THEIR IMPACT ON CCCDNA BIOLOGY. RECENT FINDINGS: WITHIN THE LAST DECADE, SUBSTANTIAL PROGRESS HAS BEEN MADE IN THE UNDERSTANDING OF CCCDNA BIOLOGY INCLUDING THE DISCOVERY OF HOST DEPENDENCY FACTORS, EPIGENETIC REGULATION OF CCCDNA TRANSCRIPTION AND IMMUNE-MEDIATED DEGRADATION. SEVERAL APPROACHES TARGETING CCCDNA EITHER IN A DIRECT OR INDIRECT MANNER ARE CURRENTLY AT THE STAGE OF DISCOVERY, PRECLINICAL OR EARLY CLINICAL DEVELOPMENT. EXAMPLES INCLUDE GENOME-EDITING APPROACHES, STRATEGIES TARGETING HOST DEPENDENCY FACTORS OR EPIGENETIC GENE REGULATION, NUCLEOCAPSID MODULATORS AND IMMUNE-MEDIATED DEGRADATION. SUMMARY: WHILE DIRECT-TARGETING CCCDNA STRATEGIES ARE STILL LARGELY AT THE PRECLINICAL STAGE OF DEVELOPMENT, CAPSID ASSEMBLY MODULATORS AND IMMUNE-BASED APPROACHES HAVE REACHED THE CLINICAL PHASE. CLINICAL TRIALS ARE ONGOING TO ASSESS THEIR EFFICACY AND SAFETY IN PATIENTS INCLUDING THEIR IMPACT ON VIRAL CCCDNA. COMBINATION THERAPIES PROVIDE ADDITIONAL OPPORTUNITIES TO OVERCOME CURRENT LIMITATIONS OF INDIVIDUAL APPROACHES. 2020 8 915 41 CHRONIC HEPATITIS B VIRUS AND HEPATITIS C VIRUS INFECTIONS AND CANCER: SYNERGY BETWEEN VIRAL AND HOST FACTORS. HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) INFECTIONS REPRESENT MAJOR CAUSES OF CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA. DESPITE INDUCING SHARED PATHOLOGICAL EVENTS LEADING TO ONCOGENIC TRANSFORMATION, THESE TWO VIRUSES PRESENT PROFOUND DIFFERENCES IN THEIR MOLECULAR FEATURES, LIFE CYCLE AND INTERPLAY WITH HOST FACTORS, WHICH SIGNIFICANTLY DIFFERENTIATE THE PROGNOSTIC AND THERAPEUTIC APPROACH TO THE RELATED DISEASES. IN THE PRESENT REVIEW, WE REPORT THE MAIN MECHANISMS INVOLVED IN THE MULTISTEP PROCESS LEADING FROM HCV/HBV INFECTION AND CANCER DEVELOPMENT, DISCUSSING SIDE-BY-SIDE THE ANALOGIES AND DIFFERENCES BETWEEN THE TWO VIRUSES. SUCH EVENTS CAN BE BROADLY CATEGORIZED INTO (A) DIRECT ONCOGENIC EFFECTS, INVOLVING INTEGRATION IN THE HOST GENOME (IN THE CASE OF HBV) AND CHROMOSOMAL INSTABILITY, INTERFERENCE WITH ONCOSUPPRESSOR PATHWAYS, INDUCTION OF OXIDATIVE STRESS, PROMOTION OF ANGIOGENESIS, EPITHELIAL-MESENCHYMAL TRANSITION, ALTERATIONS IN THE EPIGENETIC ASSET AND INTERACTION WITH NON-CODING RNAS; AND (B) INDIRECT ACTIVITIES MOSTLY MEDIATED BY HOST EVENTS, INCLUDING CHRONIC INFLAMMATION SUSTAINED BY PECULIAR CYTOKINE NETWORKS (SUCH AS INTERLEUKIN-6 AND LYMPHOTOXINS), METABOLIC DYSFUNCTIONS PROMOTED BY STEATOHEPATITIS, INTERPLAY WITH GUT MICROBIOTA AND FIBROTIC EVENTS (MAINLY IN HCV INFECTION). THIS SCENARIO SUGGESTS THAT THE INTEGRATED STUDY OF VIRAL AND HOST FACTORS MAY LEAD TO THE SUCCESSFUL DEVELOPMENT OF NOVEL BIOMARKERS AND TARGETS FOR THERAPY. 2015 9 3401 31 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 10 2240 40 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 11 6479 42 TOWARD A NEW ERA OF HEPATITIS B VIRUS THERAPEUTICS: THE PURSUIT OF A FUNCTIONAL CURE. HEPATITIS B VIRUS (HBV) INFECTION, ALTHOUGH PREVENTABLE BY VACCINATION, REMAINS A GLOBAL HEALTH PROBLEM AND A MAJOR CAUSE OF CHRONIC LIVER DISEASE. ALTHOUGH CURRENT TREATMENT STRATEGIES SUPPRESS VIRAL REPLICATION VERY EFFICIENTLY, THE OPTIMAL ENDPOINT OF HEPATITIS B SURFACE ANTIGEN (HBSAG) CLEARANCE IS RARELY ACHIEVED. MOREOVER, THE THORNY PROBLEMS OF PERSISTENT CHROMATIN-LIKE COVALENTLY CLOSED CIRCULAR DNA AND THE PRESENCE OF INTEGRATED HBV DNA IN THE HOST GENOME ARE IGNORED. THEREFORE, THE SCIENTIFIC COMMUNITY HAS FOCUSED ON DEVELOPING INNOVATIVE THERAPEUTIC APPROACHES TO ACHIEVE A FUNCTIONAL CURE OF HBV, DEFINED AS UNDETECTABLE HBV DNA AND HBSAG LOSS OVER A LIMITED TREATMENT PERIOD. A DEEPER UNDERSTANDING OF THE HBV LIFE CYCLE HAS LED TO THE INTRODUCTION OF NOVEL DIRECT-ACTING ANTIVIRALS THAT EXERT THEIR FUNCTION THROUGH MULTIPLE MECHANISMS, INCLUDING INHIBITION OF VIRAL ENTRY, TRANSCRIPTIONAL SILENCING, EPIGENETIC MANIPULATION, INTERFERENCE WITH CAPSID ASSEMBLY, AND DISRUPTION OF HBSAG RELEASE. IN PARALLEL, ANOTHER CATEGORY OF NEW DRUGS AIMS TO RESTORE DYSREGULATED IMMUNE FUNCTION IN CHRONIC HEPATITIS B ACCOMPANIED BY LETHARGIC CELLULAR AND HUMORAL RESPONSES. STIMULATION OF INNATE IMMUNITY BY PATTERN-RECOGNITION RECEPTOR AGONISTS LEADS TO UPREGULATION OF ANTIVIRAL CYTOKINE EXPRESSION AND APPEARS TO CONTRIBUTE TO HBV CONTAINMENT. IMMUNE CHECKPOINT INHIBITORS AND ADOPTIVE TRANSFER OF GENETICALLY ENGINEERED T CELLS ARE BREAKTHROUGH TECHNOLOGIES CURRENTLY BEING EXPLORED THAT MAY ELICIT POTENT HBV-SPECIFIC T-CELL RESPONSES. IN ADDITION, SEVERAL CLINICAL TRIALS ARE ATTEMPTING TO CLARIFY THE ROLE OF THERAPEUTIC VACCINATION IN THIS SETTING. ULTIMATELY, IT IS INCREASINGLY RECOGNIZED THAT ELIMINATION OF HBV REQUIRES A TREATMENT REGIMEN BASED ON A COMBINATION OF MULTIPLE DRUGS. THIS REVIEW DESCRIBES THE RATIONALE FOR PROGRESSIVE THERAPEUTIC INTERVENTIONS AND DISCUSSES THE LATEST FINDINGS IN THE FIELD OF HBV THERAPEUTICS. 2021 12 6206 20 THE INFLUENCE OF TISSUE SPATIAL GEOMETRY AND FUNCTIONAL ORGANISATION ON LIVER REGENERATION. THE ADULT LIVER EXERTS CRUCIAL FUNCTIONS, INCLUDING NUTRIENT METABOLISM AND STORAGE, BILE PRODUCTION AND DRUG DETOXIFICATION. THESE COMPLEX FUNCTIONS EXPOSE THE LIVER TO CONSTANT DAMAGE INDUCED BY TOXINS, METABOLIC INTERMEDIATES AND OXIDATIVE STRESS. HOWEVER, THE ADULT LIVER EXHIBITS AN EXCEPTIONAL REGENERATIVE POTENTIAL, WHICH ALLOWS FAST AND EFFICIENT RESTORATION OF TISSUE ARCHITECTURE AND FUNCTION BOTH AFTER TISSUE RESECTION AND TOXIC DAMAGE. TO ACCOMPLISH ITS VITAL ROLE, THE LIVER SHOWS A PECULIAR TISSUE ARCHITECTURE INTO FUNCTIONAL UNITS, WHICH FOLLOW THE GRADIENT OF OXYGEN AND NUTRIENTS WITHIN THE PARENCHYMA. MUCH LESS IS KNOWN ABOUT THE INFLUENCE OF TISSUE SPATIAL GEOMETRY AND FUNCTIONAL ORGANISATION ON ADULT LIVER REGENERATION. HERE I EXAMINE THE EXPERIMENTAL EVIDENCE IN MOUSE MODELS SHOWING THAT THE SPATIAL ORGANISATION OF THE EPITHELIAL AND MESENCHYMAL COMPARTMENTS PLAYS A KEY ROLE IN LIVER REGENERATION AND FAVOURS THE ESTABLISHMENT OF REGENERATIVE ADULT LIVER PROGENITORS FOLLOWING LIVER INJURY. I ALSO DISCUSS THE ADVANTAGES AND LIMITATIONS OF HUMAN AND MOUSE 3D HEPATIC ORGANOID SYSTEMS, WHICH RECAPITULATE KEY ASPECTS OF LIVER FUNCTION AND ARCHITECTURE, AS MODELS OF LIVER REGENERATION AND DISEASE. FINALLY, I ANALYSE THE ROLE OF THE YAP/TAZ TRANSCRIPTIONAL CO-ACTIVATORS AS A CENTRAL HUB SENSING THE EXTRA-CELLULAR MATRIX (ECM), METABOLIC AND EPIGENETIC REMODELLING THAT REGULATE LIVER REGENERATION AND PROMOTE LIVER DISEASE, SUCH AS FIBROSIS, CHRONIC LIVER DISEASE AND LIVER CANCER. TOGETHER, THE FINDINGS SUMMARISED HERE DEMONSTRATE THAT LOCAL PHYSICAL AND FUNCTIONAL CELLULAR INTERACTIONS DETERMINED BY THE LIVER PECULIAR SPATIAL GEOMETRY, PLAY A CRUCIAL ROLE IN LIVER REGENERATION, AND THAT THEIR ALTERATIONS HAVE IMPORTANT IMPLICATIONS FOR HUMAN LIVER DISEASE. 2022 13 5936 30 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 14 3259 33 HEPATITIS C VIRUS AND HEPATOCELLULAR CARCINOMA: WHEN THE HOST LOSES ITS GRIP. CHRONIC INFECTION WITH HEPATITIS C VIRUS (HCV) IS A MAJOR CAUSE OF HEPATOCELLULAR CARCINOMA (HCC). NOVEL TREATMENTS WITH DIRECT-ACTING ANTIVIRALS ACHIEVE HIGH RATES OF SUSTAINED VIROLOGIC RESPONSE; HOWEVER, THE HCC RISK REMAINS ELEVATED IN CURED PATIENTS, ESPECIALLY THOSE WITH ADVANCED LIVER DISEASE. LONG-TERM HCV INFECTION CAUSES A PERSISTENT AND ACCUMULATING DAMAGE OF THE LIVER DUE TO A COMBINATION OF DIRECT AND INDIRECT PRO-ONCOGENIC MECHANISMS. THIS REVIEW DESCRIBES THE PROCESSES INVOLVED IN VIRUS-INDUCED DISEASE PROGRESSION BY VIRAL PROTEINS, DERAILED SIGNALING, IMMUNITY, AND PERSISTENT EPIGENETIC DEREGULATION, WHICH MAY BE INSTRUMENTAL TO DEVELOP URGENTLY NEEDED PROGNOSTIC BIOMARKERS AND AS TARGETS FOR NOVEL CHEMOPREVENTIVE THERAPIES. 2020 15 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 16 5365 28 RECENT ADVANCES IN HEPATITIS B TREATMENT. HEPATITIS B VIRUS INFECTION AFFECTS OVER 250 MILLION CHRONIC CARRIERS, CAUSING MORE THAN 800,000 DEATHS ANNUALLY, ALTHOUGH A SAFE AND EFFECTIVE VACCINE IS AVAILABLE. CURRENTLY USED ANTIVIRAL AGENTS, PEGYLATED INTERFERON AND NUCLEOS(T)IDE ANALOGUES, HAVE MAJOR DRAWBACKS AND FAIL TO COMPLETELY ERADICATE THE VIRUS FROM INFECTED CELLS. THUS, ACHIEVING A "FUNCTIONAL CURE" OF THE INFECTION REMAINS A REAL CHALLENGE. RECENT FINDINGS CONCERNING THE VIRAL REPLICATION CYCLE HAVE LED TO DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES INCLUDING VIRAL ENTRY INHIBITORS, EPIGENETIC CONTROL OF CCCDNA, IMMUNE MODULATORS, RNA INTERFERENCE TECHNIQUES, RIBONUCLEASE H INHIBITORS, AND CAPSID ASSEMBLY MODULATORS. PROMISING PRECLINICAL RESULTS HAVE BEEN OBTAINED, AND THE LEADING MOLECULES UNDER DEVELOPMENT HAVE ENTERED CLINICAL EVALUATION. THIS REVIEW SUMMARIZES THE KEY STEPS OF THE HBV LIFE CYCLE, EXAMINES THE CURRENTLY APPROVED ANTI-HBV DRUGS, AND ANALYZES NOVEL HBV TREATMENT REGIMENS. 2021 17 5689 39 SILENCING HEPATITIS B VIRUS COVALENTLY CLOSED CIRCULAR DNA: THE POTENTIAL OF AN EPIGENETIC THERAPY APPROACH. GLOBAL PROPHYLACTIC VACCINATION PROGRAMMES HAVE HELPED TO CURB NEW HEPATITIS B VIRUS (HBV) INFECTIONS. HOWEVER, IT IS ESTIMATED THAT NEARLY 300 MILLION PEOPLE ARE CHRONICALLY INFECTED AND HAVE A HIGH RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA. AS SUCH, HBV REMAINS A SERIOUS HEALTH PRIORITY AND THE DEVELOPMENT OF NOVEL CURATIVE THERAPEUTICS IS URGENTLY NEEDED. CHRONIC HBV INFECTION HAS BEEN ATTRIBUTED TO THE PERSISTENCE OF THE COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) WHICH ESTABLISHES ITSELF AS A MINICHROMOSOME IN THE NUCLEUS OF HEPATOCYTES. AS THE VIRAL TRANSCRIPTION INTERMEDIATE, THE CCCDNA IS RESPONSIBLE FOR PRODUCING NEW VIRIONS AND PERPETUATING INFECTION. HBV IS DEPENDENT ON VARIOUS HOST FACTORS FOR CCCDNA FORMATION AND THE MINICHROMOSOME IS AMENABLE TO EPIGENETIC MODIFICATIONS. TWO HBV PROTEINS, X (HBX) AND CORE (HBC) PROMOTE VIRAL REPLICATION BY MODULATING THE CCCDNA EPIGENOME AND REGULATING HOST CELL RESPONSES. THIS INCLUDES VIRAL AND HOST GENE EXPRESSION, CHROMATIN REMODELING, DNA METHYLATION, THE ANTIVIRAL IMMUNE RESPONSE, APOPTOSIS, AND UBIQUITINATION. ELIMINATION OF THE CCCDNA MINICHROMOSOME WOULD RESULT IN A STERILIZING CURE; HOWEVER, THIS MAY BE DIFFICULT TO ACHIEVE. EPIGENETIC THERAPIES COULD PERMANENTLY SILENCE THE CCCDNA MINICHROMOSOME AND PROMOTE A FUNCTIONAL CURE. THIS REVIEW EXPLORES THE CCCDNA EPIGENOME, HOW HOST AND VIRAL FACTORS INFLUENCE TRANSCRIPTION, AND THE RECENT EPIGENETIC THERAPIES AND EPIGENOME ENGINEERING APPROACHES THAT HAVE BEEN DESCRIBED. 2021 18 3394 35 HOST EPIGENETIC ALTERATIONS AND HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST FREQUENT PRIMARY MALIGNANCY OF THE LIVER AND A LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE. ALTHOUGH MUCH PROGRESS HAS BEEN MADE IN HCC DRUG DEVELOPMENT IN RECENT YEARS, TREATMENT OPTIONS REMAIN LIMITED. THE MAJOR CAUSE OF HCC IS CHRONIC HEPATITIS B VIRUS (HBV) INFECTION. DESPITE THE EXISTENCE OF A VACCINE, MORE THAN 250 MILLION INDIVIDUALS ARE CHRONICALLY INFECTED BY HBV. CURRENT ANTIVIRAL THERAPIES CAN REPRESS VIRAL REPLICATION BUT TO DATE THERE IS NO CURE FOR CHRONIC HEPATITIS B. OF NOTE, INHIBITION OF VIRAL REPLICATION REDUCES BUT DOES NOT ELIMINATE THE RISK OF HCC DEVELOPMENT. HBV CONTRIBUTES TO LIVER CARCINOGENESIS BY DIRECT AND INDIRECT EFFECTS. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE OF HBV-INDUCED HOST EPIGENETIC ALTERATIONS AND THEIR ASSOCIATION WITH HCC, WITH AN EMPHASIS ON THE INTERACTIONS BETWEEN HBV PROTEINS AND THE HOST CELL EPIGENETIC MACHINERY LEADING TO MODULATION OF GENE EXPRESSION. 2021 19 2324 36 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 20 6637 23 UNRAVELING THE COMPLEXITY OF HEPATITIS B VIRUS: FROM MOLECULAR UNDERSTANDING TO THERAPEUTIC STRATEGY IN 50 YEARS. HEPATITIS B VIRUS (HBV) IS A WELL-KNOWN HEPADNAVIRUS WITH A DOUBLE-STRANDED CIRCULAR DNA GENOME. ALTHOUGH HBV WAS FIRST DESCRIBED APPROXIMATELY 50 YEARS AGO, THE PRECISE MECHANISMS OF HBV INFECTION AND EFFECTIVE THERAPEUTIC STRATEGIES REMAIN UNCLEAR. HERE, WE FOCUS ON SUMMARIZING THE COMPLICATED MECHANISMS OF HBV REPLICATION AND INFECTION, AS WELL AS GENOMIC FACTORS AND EPIGENETIC REGULATION. ADDITIONALLY, WE DISCUSS IN VIVO MODELS OF HBV, AS WELL AS DIAGNOSIS, PREVENTION AND THERAPEUTIC DRUGS FOR HBV. TOGETHER, THE DATA IN THIS 50-YEAR REVIEW MAY PROVIDE NEW CLUES TO ELUCIDATE MOLECULAR MECHANISMS OF HBV PATHOGENESIS AND SHED NEW LIGHT ON THE FUTURE HBV THERAPIES. 2013