1 6523 122 TRANSCRIPTIONAL AND EPIGENETIC REGULATORY MECHANISMS AFFECTING HTLV-1 PROVIRUS. HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-1) IS A RETROVIRUS ASSOCIATED WITH HUMAN DISEASES, SUCH AS ADULT T-CELL LEUKEMIA (ATL) AND HTLV-1-ASSOCIATED MYELOPATHY/TROPIC SPASTIC PARAPARESIS (HAM/TSP). AS A RETROVIRUS, ITS LIFE CYCLE INCLUDES A STEP WHERE HTLV-1 IS INTEGRATED INTO THE HOST GENOMIC DNA AND FORMS PROVIRAL DNA. IN THE CHRONIC PHASE OF THE INFECTION, HTLV?1 IS KNOWN TO PROLIFERATE AS A PROVIRUS VIA THE MITOTIC DIVISION OF THE INFECTED HOST CELLS. THERE ARE GENERALLY TENS OF THOUSANDS OF INFECTED CLONES WITHIN AN INFECTED INDIVIDUAL. THEY EXIST NOT ONLY IN PERIPHERAL BLOOD, BUT ALSO IN VARIOUS LYMPHOID ORGANS. VIRAL PROTEINS ENCODED IN HTLV-1 GENOME PLAY A ROLE IN THE PROLIFERATION AND SURVIVAL OF THE INFECTED CELLS. AS IS THE CASE WITH OTHER CHRONIC VIRAL INFECTIONS, HTLV-1 GENE EXPRESSION INDUCES THE ACTIVATION OF THE HOST IMMUNITY AGAINST THE VIRUS. THUS, THE TRANSCRIPTION FROM HTLV-1 PROVIRUS NEEDS TO BE CONTROLLED IN ORDER TO EVADE THE HOST IMMUNE SURVEILLANCE. THERE SHOULD BE A DYNAMIC AND COMPLEX REGULATION IN VIVO, WHERE AN EQUILIBRIUM BETWEEN VIRAL ANTIGEN EXPRESSION AND HOST IMMUNE SURVEILLANCE IS ACHIEVED. THE MECHANISMS REGULATING VIRAL GENE EXPRESSION FROM THE PROVIRUS ARE A KEY TO UNDERSTANDING THE PERSISTENT/LATENT INFECTION WITH HTLV-1 AND ITS PATHOGENESIS. IN THIS ARTICLE, WE WOULD LIKE TO REVIEW OUR CURRENT UNDERSTANDING ON THIS TOPIC. 2016 2 3340 48 HISTONE DEACETYLASE MEDIATED TRANSCRIPTIONAL ACTIVATION REDUCES PROVIRAL LOADS IN HTLV-1 ASSOCIATED MYELOPATHY/TROPICAL SPASTIC PARAPARESIS PATIENTS. EPIGENETIC MODIFICATIONS OF CHROMATIN MAY PLAY A ROLE IN MAINTAINING VIRAL LATENCY AND THUS PERSISTENCE OF THE HUMAN T-LYMPHOTROPIC VIRUS TYPE 1 (HTLV-1), WHICH IS RESPONSIBLE FOR HTLV-ASSOCIATED MYELOPATHY/TROPICAL SPASTIC PARAPARESIS (HAM/TSP). A MAJOR DETERMINANT OF DISEASE PROGRESSION IS INCREASED PERIPHERAL BLOOD PROVIRAL LOAD (PVL), POSSIBLY VIA THE ACCUMULATION OF INFECTED CELLS IN THE CENTRAL NERVOUS SYSTEM (CNS) CREATING A DAMAGING INFLAMMATORY RESPONSE. CURRENT THERAPEUTIC APPROACHES THAT FOCUS ON REDUCING EITHER CELL PROLIFERATION, VIRAL REPLICATION, OR TISSUE INVASION ARE STILL UNSATISFACTORY. CONTRASTING WITH THESE INHIBITORY STRATEGIES, WE EVALUATED THE EFFICACY OF A NOVEL APPROACH AIMED, PARADOXICALLY, AT ACTIVATING VIRAL GENE EXPRESSION TO EXPOSE VIRUS-POSITIVE CELLS TO THE HOST IMMUNE RESPONSE. WE USED VALPROATE (VPA), A HISTONE DEACETYLASE INHIBITOR THAT HAS BEEN USED FOR DECADES AS A CHRONIC, SAFE TREATMENT FOR EPILEPTIC DISORDERS. BASED ON IN VITRO AND IN VIVO DATA, WE PROVIDE EVIDENCE THAT TRANSIENT ACTIVATION OF THE LATENT VIRAL RESERVOIR CAUSES ITS COLLAPSE, A PROCESS THAT MAY ALLEVIATE THE CONDITION OF HAM/TSP. THIS REPRESENTS THE FIRST SUCH APPROACH TO TREATING HAM/TSP, USING GENE ACTIVATION THERAPY TO TILT THE HOST-PATHOGEN BALANCE IN FAVOR OF AN EXISTING ANTIVIRAL RESPONSE. THIS TRIAL IS REGISTERED AT HTTP://CLINICALTRIALS.GOV/AS NO. NCT00519181. 2007 3 6789 27 [CURRENT STATUS OF ATL RESEARCH: EFFORTS FOR PREVENTION AND PRECISION MEDICINE FOR ATL]. THE INTRODUCTION OF NEW AGENTS AND HEMATOPOIETIC STEM CELL TRANSPLANTATION INTO THE TREATMENT OF ATL HAS ACTIVATED ITS CLINICAL RESEARCH. HOWEVER, THE PROGNOSIS OF ATL REMAINS POOR COMPARED WITH THOSE OF OTHER LEUKEMIAS AND LYMPHOMAS. THUS, SEEMINGLY WE HAVE TO RECONSIDER A NEW STRATEGY OF ATL THERAPY BASED ON ITS UNIQUE CHARACTERISTICS. HTLV-1 INFECTION OF T CELLS RESULTS IN CLONAL PROLIFERATION OF INFECTED CELLS THAT ACCUMULATE GENETIC AND EPIGENETIC ABNORMALITIES BEFORE THE ONSET OF ATL. THEREFORE, THE TREATMENT STRATEGY SHOULD INCLUDE THE PREVENTION OF HTLV-1 INFECTION AND ATL DEVELOPMENT IN ADDITION TO PRECISION MEDICINE BASED ON THE STRATIFICATION OF ATL CASES BY BIOMARKERS THAT DISCRIMINATE CLINICAL STAGES OF ATL. I SUMMARIZE HERE THE RECENT PROGRESS IN ATL RESEARCH FOCUSING ON THE BIOMOLECULAR ABNORMALITIES THAT LEAD TO CLONAL EXPANSION AND MALIGNANT TRANSFORMATION OF HTLV-1-INFECTED T CELLS. APPARENTLY, ONE OF THE BASES FOR THE PREVENTION OF ATL IS TO ESTABLISH A DISEASE ENTITY OF "CHRONIC ACTIVE HTLV-1 INFECTION" THAT DEFINES HIGH-RISK CARRIERS FOR ATL DEVELOPMENT AND ENABLES PREVENTIVE INTERVENTION. 2017 4 2073 39 EPIGENETIC CROSSTALK IN CHRONIC INFECTION WITH HIV-1. HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV-1) REPLICATES THROUGH THE INTEGRATION OF ITS VIRAL DNA INTO THE GENOME OF HUMAN IMMUNE TARGET CELLS. CHRONICALLY INFECTED INDIVIDUALS THUS CARRY A GENOMIC BURDEN OF VIRUS-DERIVED SEQUENCES THAT PERSISTS THROUGH ANTIRETROVIRAL THERAPY. THIS BURDEN CONSISTS OF A SMALL FRACTION OF INTACT, BUT TRANSCRIPTIONALLY SILENCED, I.E. LATENT, VIRAL GENOMES AND A DOMINANT FRACTION OF DEFECTIVE SEQUENCES. REMARKABLY, ALL VIRAL-DERIVED SEQUENCES ARE SUBJECT TO INTERACTION WITH HOST CELLULAR PHYSIOLOGY AT VARIOUS LEVELS. IN THIS REVIEW, WE FOCUS ON EPIGENETIC ASPECTS OF THIS INTERACTION. WE PROVIDE A COMPREHENSIVE OVERVIEW OF HOW EPIGENETIC MECHANISMS CONTRIBUTE TO ESTABLISHMENT AND MAINTENANCE OF HIV-1 GENE REPRESSION DURING LATENCY. WE FURTHERMORE SUMMARIZE FINDINGS INDICATING THAT HIV-1 INFECTION LEADS TO CHANGES IN THE EPIGENOME OF TARGET AND BYSTANDER IMMUNE CELLS. FINALLY, WE DISCUSS HOW AN IMPROVED UNDERSTANDING OF EPIGENETIC FEATURES AND MECHANISMS INVOLVED IN HIV-1 INFECTION COULD BE EXPLOITED FOR CLINICAL USE. 2020 5 6590 38 TUMOR SUPPRESSOR INACTIVATION IN THE PATHOGENESIS OF ADULT T-CELL LEUKEMIA. TUMOR SUPPRESSOR FUNCTIONS ARE ESSENTIAL TO CONTROL CELLULAR PROLIFERATION, TO ACTIVATE THE APOPTOSIS OR SENESCENCE PATHWAY TO ELIMINATE UNWANTED CELLS, TO LINK DNA DAMAGE SIGNALS TO CELL CYCLE ARREST CHECKPOINTS, TO ACTIVATE APPROPRIATE DNA REPAIR PATHWAYS, AND TO PREVENT THE LOSS OF ADHESION TO INHIBIT INITIATION OF METASTASES. THEREFORE, TUMOR SUPPRESSOR GENES ARE INDISPENSABLE TO MAINTAINING GENETIC AND GENOMIC INTEGRITY. CONSEQUENTLY, INACTIVATION OF TUMOR SUPPRESSORS BY SOMATIC MUTATIONS OR EPIGENETIC MECHANISMS IS FREQUENTLY ASSOCIATED WITH TUMOR INITIATION AND DEVELOPMENT. IN CONTRAST, REACTIVATION OF TUMOR SUPPRESSOR FUNCTIONS CAN EFFECTIVELY REVERSE THE TRANSFORMED PHENOTYPE AND LEAD TO CELL CYCLE ARREST OR DEATH OF CANCEROUS CELLS AND BE USED AS A THERAPEUTIC STRATEGY. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL) IS AN AGGRESSIVE LYMPHOPROLIFERATIVE DISEASE ASSOCIATED WITH INFECTION OF CD4 T CELLS BY THE HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-I). HTLV-I-ASSOCIATED T-CELL TRANSFORMATION IS THE RESULT OF A MULTISTEP ONCOGENIC PROCESS IN WHICH THE VIRUS INITIALLY INDUCES CHRONIC T-CELL PROLIFERATION AND ALTERS CELLULAR PATHWAYS RESULTING IN THE ACCUMULATION OF GENETIC DEFECTS AND THE DEREGULATED GROWTH OF VIRALLY INFECTED CELLS. THIS REVIEW WILL FOCUS ON THE CURRENT KNOWLEDGE OF THE GENETIC AND EPIGENETIC MECHANISMS REGULATING THE INACTIVATION OF TUMOR SUPPRESSORS IN THE PATHOGENESIS OF HTLV-I. 2015 6 6706 28 VIRAL GENE PRODUCTS ACTIVELY PROMOTE LATENT INFECTION BY EPIGENETIC SILENCING MECHANISMS. MANY VIRUSES UNDERGO AN ACUTE INFECTION IN THE HOST ORGANISM AND THEN ARE CLEARED BY THE ENSUING HOST IMMUNE RESPONSE, BUT OTHER VIRUSES ESTABLISH A PERSISTENT INFECTION INVOLVING A LATENT INFECTION OR A CHRONIC INFECTION. LATENT INFECTION BY THE HERPESVIRUSES OR HUMAN IMMUNODEFICIENCY VIRUS INVOLVES EPIGENETIC SILENCING OF THE DNA GENOME OR PROVIRAL GENOME, RESPECTIVELY. LATENT INFECTION WAS PREVIOUSLY THOUGHT TO BE A DEFAULT PATHWAY RESULTING FROM INFECTION OF A NONPERMISSIVE CELL, BUT RECENT STUDIES HAVE SHOWN THAT VIRAL GENE PRODUCTS CAN PROMOTE EPIGENETIC SILENCING AND LATENT INFECTION. THIS REVIEW WILL SUMMARIZE THE VIRAL GENE PRODUCTS THAT HAVE BEEN SHOWN TO PROMOTE EPIGENETIC SILENCING OF THE GENOMES AND THEIR POTENTIAL FOR THERAPEUTICS TO TARGET THESE VIRAL GENE PRODUCTS AND DISRUPT OR LOCK IN LATENT INFECTION. 2017 7 4760 40 NOVEL TREATMENTS OF ADULT T CELL LEUKEMIA LYMPHOMA. ADULT T CELL LEUKEMIA-LYMPHOMA (ATL) IS AN AGGRESSIVE MALIGNANCY SECONDARY TO CHRONIC INFECTION WITH THE HUMAN T CELL LEUKEMIA VIRUS TYPE I (HTLV-I) RETROVIRUS. ATL CARRIES A DISMAL PROGNOSIS. ATL CLASSIFIES INTO FOUR SUBTYPES (ACUTE, LYMPHOMA, CHRONIC, AND SMOLDERING) WHICH DISPLAY DIFFERENT CLINICAL FEATURES, PROGNOSIS AND RESPONSE TO THERAPY, HENCE REQUIRING DIFFERENT CLINICAL MANAGEMENT. SMOLDERING AND CHRONIC SUBTYPES RESPOND WELL TO ANTIRETROVIRAL THERAPY USING THE COMBINATION OF ZIDOVUDINE (AZT) AND INTERFERON-ALPHA (IFN) WITH A SIGNIFICANT PROLONGATION OF SURVIVAL. CONVERSELY, THE WATCH AND WAIT STRATEGY OR CHEMOTHERAPY FOR THESE INDOLENT SUBTYPES ALLIES WITH A POOR LONG-TERM OUTCOME. ACUTE ATL IS ASSOCIATED WITH CHEMO-RESISTANCE AND DISMAL PROGNOSIS. LYMPHOMA SUBTYPES RESPOND BETTER TO INTENSIVE CHEMOTHERAPY BUT SURVIVAL REMAINS POOR. ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) RESULTS IN LONG-TERM SURVIVAL IN ROUGHLY ONE THIRD OF TRANSPLANTED PATIENTS BUT ONLY A SMALL PERCENTAGE OF PATIENTS CAN MAKE IT TO TRANSPLANT. OVERALL, CURRENT TREATMENTS OF AGGRESSIVE ATL ARE NOT SATISFACTORY. PROGNOSIS OF REFRACTORY OR RELAPSED PATIENTS IS DISMAL WITH SOME ENCOURAGING RESULTS WHEN USING LENALIDOMIDE OR MOGAMULIZUMAB. TO OVERCOME RESISTANCE AND PREVENT RELAPSE, PRECLINICAL OR PILOT CLINICAL STUDIES USING TARGETED THERAPIES SUCH AS ARSENIC/IFN, MONOCLONAL ANTIBODIES, EPIGENETIC THERAPIES ARE PROMISING BUT WARRANT FURTHER CLINICAL INVESTIGATION. ANTI-ATL VACCINES INCLUDING TAX PEPTIDE-PULSED DENDRITIC CELLS, INDUCED TAX-SPECIFIC CTL RESPONSES IN ATL PATIENTS. FINALLY, BASED ON THE PROGRESS IN UNDERSTANDING THE PATHOPHYSIOLOGY OF ATL, AND THE RISK-ADAPTED TREATMENT APPROACHES TO DIFFERENT ATL SUBTYPES, TREATMENT STRATEGIES OF ATL SHOULD TAKE INTO ACCOUNT THE HOST IMMUNE RESPONSES AND THE HOST MICROENVIRONMENT INCLUDING HTLV-1 INFECTED NON-MALIGNANT CELLS. HEREIN, WE WILL PROVIDE A SUMMARY OF NOVEL TREATMENTS OF ATL IN VITRO, IN VIVO, AND IN EARLY CLINICAL TRIALS. 2020 8 3379 32 HIV LATENCY AND THE NONCODING RNA THERAPEUTIC LANDSCAPE. THE HUMAN IMMUNODEFICIENCY VIRUS (HIV) BELONGS TO THE SUBFAMILY OF LENTIVIRUSES THAT ARE CHARACTERIZED BY LONG INCUBATION PERIODS AND CHRONIC, PERSISTENT INFECTION. THE VIRUS INTEGRATES INTO THE GENOME OF INFECTED CD4+ CELLS AND, IN A SUBPOPULATION OF CELLS, ADOPTS A TRANSCRIPTIONALLY SILENT STATE, A PROCESS REFERRED TO A VIRAL LATENCY. THIS PROPERTY MAKES IT EXCEEDINGLY DIFFICULT TO THERAPEUTICALLY TARGET THE VIRUS AND ERADICATE INFECTION. IF LEFT UNTREATED, THE INEXORABLE DEMISE OF THE INFECTED INDIVIDUAL'S IMMUNE SYSTEM ENSUES, A CAUSAL RESULT OF ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS). LATENTLY INFECTED CELLS PROVIDE A RESERVOIR THAT MAINTAINS VIRAL INFECTION INDEFINITELY. IN THIS CHAPTER WE EXPLORE THE ROLE OF NONCODING RNAS IN HIV INFECTION AND IN THE ESTABLISHMENT AND MAINTENANCE OF VIRAL LATENCY. BOTH SHORT AND LONG NONCODING RNAS ARE ENDOGENOUS MODULATORS OF EPIGENETIC REGULATION IN HUMAN CELLS AND PLAY AN ACTIVE ROLE IN GENE EXPRESSION. LASTLY, WE EXPLORE THERAPEUTIC MODALITIES BASED ON EXPRESSED RNAS THAT ARE CAPABLE OF COUNTERING INFECTION, TRANSCRIPTIONALLY REGULATING THE VIRUS, AND SUPPRESSING OR ACTIVATING THE LATENT STATE. 2015 9 6044 33 THE COMPLEX BIOLOGY OF HUMAN CYTOMEGALOVIRUS LATENCY. WHILE MANY VIRAL INFECTIONS ARE LIMITED AND EVENTUALLY RESOLVED BY THE HOST IMMUNE RESPONSE OR BY DEATH OF THE HOST, OTHER VIRUSES ESTABLISH LONG-TERM RELATIONSHIPS WITH THE HOST BY WAY OF A PERSISTENT INFECTION, THAT RANGE FROM CHRONIC VIRUSES THAT MAY BE EVENTUALLY CLEARED TO THOSE THAT ESTABLISH LIFE-LONG PERSISTENT OR LATENT INFECTION. VIRUSES INFECTING HOSTS FROM BACTERIA TO HUMANS ESTABLISH QUIESCENT INFECTIONS THAT MUST BE REACTIVATED TO PRODUCE PROGENY. FOR MAMMALIAN VIRUSES, MOST NOTABLY HERPESVIRUSES, THIS QUIESCENT MAINTENANCE OF VIRAL GENOMES IN THE ABSENCE OF VIRUS REPLICATION IS REFERRED TO AS LATENCY. THE LATENT STRATEGY ALLOWS THE VIRUS TO PERSIST QUIESCENTLY WITHIN A SINGLE HOST UNTIL CONDITIONS INDICATE A NEED TO REACTIVATE TO REACH A NEW HOST OR, TO RE-SEED A RESERVOIR WITHIN THE HOST. HERE, I REVIEW COMMON THEMES IN VIRAL STRATEGIES TO REGULATE THE LATENT CYCLE AND REACTIVATE FROM IT RANGING FROM BACTERIOPHAGE TO HERPESVIRUSES WITH A FOCUS ON HUMAN CYTOMEGALOVIRUS (HCMV). THEMES CENTRAL TO HERPESVIRUS LATENCY INCLUDE, EPIGENETIC REPRESSION OF VIRAL GENE EXPRESSION AND MECHANISMS TO REGULATE HOST SIGNALING AND SURVIVAL. CRITICAL TO THE SUCCESS OF A LATENT PROGRAM ARE MECHANISMS BY WHICH THE VIRUS CAN "SENSE" FLUCTUATIONS IN HOST BIOLOGY (WITHIN THE HOST) OR ENVIRONMENT (OUTSIDE THE HOST) AND MAKE APPROPRIATE "DECISIONS" TO MAINTAIN LATENCY OR RE-INITIATE THE REPLICATIVE PROGRAM. THE SIGNALS OR ENVIRONMENTS THAT INDICATE THE ESTABLISHMENT OF A LATENT STATE, THE VERY NATURE OF THE LATENT STATE, AS WELL AS THE SIGNALS DRIVING REACTIVATION HAVE BEEN TOPICS OF INTENSE STUDY FROM BACTERIOPHAGE TO HUMAN VIRUSES, AS THESE QUESTIONS ENCOMPASS THE HEIGHT OF COMPLEXITY IN VIRUS-HOST INTERACTIONS-WHERE THE HOST AND THE VIRUS COEXIST. 2022 10 2663 26 EPSTEIN-BARR VIRUS PROMOTES B CELL LYMPHOMAS BY MANIPULATING THE HOST EPIGENETIC MACHINERY. DURING THE PAST DECADE, THE RAPID DEVELOPMENT OF HIGH-THROUGHPUT NEXT-GENERATION SEQUENCING TECHNOLOGIES HAS SIGNIFICANTLY REINFORCED OUR UNDERSTANDING OF THE ROLE OF EPIGENETICS IN HEALTH AND DISEASE. ALTERED FUNCTIONS OF EPIGENETIC MODIFIERS LEAD TO THE DISRUPTION OF THE HOST EPIGENOME, ULTIMATELY INDUCING CARCINOGENESIS AND DISEASE PROGRESSION. EPSTEIN-BARR VIRUS (EBV) IS AN ENDEMIC HERPESVIRUS THAT IS ASSOCIATED WITH SEVERAL MALIGNANT TUMOURS, INCLUDING B-CELL RELATED LYMPHOMAS. IN EBV-INFECTED CELLS, THE EPIGENOMIC LANDSCAPE IS EXTENSIVELY RESHAPED BY VIRAL ONCOPROTEINS, WHICH DIRECTLY INTERACT WITH EPIGENETIC MODIFIERS AND MODULATE THEIR FUNCTION. THIS PROCESS IS FUNDAMENTAL FOR THE EBV LIFE CYCLE, PARTICULARLY FOR THE ESTABLISHMENT AND MAINTENANCE OF LATENCY IN B CELLS; HOWEVER, THE ALTERATION OF THE HOST EPIGENETIC MACHINERY ALSO CONTRIBUTES TO THE DYSREGULATED EXPRESSION OF SEVERAL CELLULAR GENES, INCLUDING TUMOUR SUPPRESSOR GENES, WHICH CAN DRIVE LYMPHOMA DEVELOPMENT. THIS REVIEW OUTLINES THE MOLECULAR MECHANISMS UNDERLYING THE EPIGENETIC MANIPULATION INDUCED BY EBV THAT LEAD TO TRANSFORMED B CELLS, AS WELL AS NOVEL THERAPEUTIC INTERVENTIONS TO TARGET EBV-ASSOCIATED B-CELL LYMPHOMAS. 2020 11 1057 35 CLINICAL MANIFESTATIONS AND EPIGENETIC REGULATION OF ORAL HERPESVIRUS INFECTIONS. THE ORAL CAVITY IS OFTEN THE FIRST SITE WHERE VIRUSES INTERACT WITH THE HUMAN BODY. THE ORAL EPITHELIUM IS A MAJOR SITE OF VIRAL ENTRY, REPLICATION AND SPREAD TO OTHER CELL TYPES, WHERE CHRONIC INFECTION CAN BE ESTABLISHED. IN ADDITION, SALIVA HAS BEEN SHOWN AS A PRIMARY ROUTE OF PERSON-TO-PERSON TRANSMISSION FOR MANY VIRUSES. FROM A CLINICAL PERSPECTIVE, VIRAL INFECTION CAN LEAD TO SEVERAL ORAL MANIFESTATIONS, RANGING FROM COMMON INTRAORAL LESIONS TO TUMORS. DESPITE THE CLINICAL AND BIOLOGICAL RELEVANCE OF INITIAL ORAL INFECTION, LITTLE IS KNOWN ABOUT THE MECHANISM OF REGULATION OF THE VIRAL LIFE CYCLE IN THE ORAL CAVITY. SEVERAL VIRUSES UTILIZE HOST EPIGENETIC MACHINERY TO PROMOTE THEIR OWN LIFE CYCLE. IMPORTANTLY, VIRAL HIJACKING OF HOST CHROMATIN-MODIFYING ENZYMES CAN ALSO LEAD TO THE DYSREGULATION OF HOST FACTORS AND IN THE CASE OF ONCOGENIC VIRUSES MAY ULTIMATELY PLAY A ROLE IN PROMOTING TUMORIGENESIS. GIVEN THE KNOWN ROLES OF EPIGENETIC REGULATION OF VIRAL INFECTION, EPIGENETIC-TARGETED ANTIVIRAL THERAPY HAS BEEN RECENTLY EXPLORED AS A THERAPEUTIC OPTION FOR CHRONIC VIRAL INFECTION. IN THIS REVIEW, WE HIGHLIGHT THREE HERPESVIRUSES WITH KNOWN ROLES IN ORAL INFECTION, INCLUDING HERPES SIMPLEX VIRUS TYPE 1, EPSTEIN-BARR VIRUS AND KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS. WE FOCUS ON THE RESPECTIVE ORAL CLINICAL MANIFESTATIONS OF THESE VIRUSES AND THEIR EPIGENETIC REGULATION, WITH A SPECIFIC EMPHASIS ON THE VIRAL LIFE CYCLE IN THE ORAL EPITHELIUM. 2021 12 6365 35 THE ROLE OF METABOLIC DYSFUNCTION IN T-CELL EXHAUSTION DURING CHRONIC VIRAL INFECTION. T CELLS ARE IMPORTANT COMPONENTS OF ADAPTIVE IMMUNITY THAT PROTECT THE HOST AGAINST INVADING PATHOGENS DURING INFECTION. UPON RECOGNIZING THE ACTIVATION SIGNALS, NAIVE AND/OR MEMORY T CELLS WILL INITIATE CLONAL EXPANSION, TRIGGER DIFFERENTIATION INTO EFFECTOR POPULATIONS AND TRAFFIC TO THE INFLAMED SITES TO ELIMINATE PATHOGENS. HOWEVER, IN CHRONIC VIRAL INFECTIONS, SUCH AS THOSE CAUSED BY HUMAN IMMUNODEFICIENCY VIRUS (HIV), HEPATITIS B AND C (HBV AND HCV), T CELLS EXHIBIT IMPAIRED FUNCTION AND BECOME DIFFICULT TO CLEAR PATHOGENS IN A STATE KNOWN AS T-CELL EXHAUSTION. THE ACTIVATION AND FUNCTION PERSISTENCE OF T CELLS DEMAND FOR DYNAMIC CHANGES IN CELLULAR METABOLISM TO MEET THEIR BIOENERGETIC AND BIOSYNTHETIC DEMANDS, ESPECIALLY THE AUGMENTATION OF AEROBIC GLYCOLYSIS, WHICH NOT ONLY PROVIDE EFFICIENT ENERGY GENERATION, BUT ALSO FUEL MULTIPLE BIOCHEMICAL INTERMEDIATES THAT ARE ESSENTIAL FOR NUCLEOTIDE, AMINO ACID, FATTY ACID SYNTHESIS AND MITOCHONDRIA FUNCTION. CHANGES IN CELLULAR METABOLISM ALSO AFFECT THE FUNCTION OF EFFECTORS T CELLS THROUGH MODIFYING EPIGENETIC SIGNATURES. IT IS WIDELY ACCEPTED THAT THE DYSFUNCTION OF T CELL METABOLISM CONTRIBUTES GREATLY TO T-CELL EXHAUSTION. HERE, WE REVIEWED RECENT FINDINGS ON T CELLS METABOLISM UNDER CHRONIC VIRAL INFECTION, SEEKING TO REVEAL THE ROLE OF METABOLIC DYSFUNCTION PLAYED IN T-CELL EXHAUSTION. 2022 13 6641 30 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 14 2056 27 EPIGENETIC CONTROL OF CD8(+) T CELL DIFFERENTIATION. UPON STIMULATION, SMALL NUMBERS OF NAIVE CD8(+) T CELLS PROLIFERATE AND DIFFERENTIATE INTO A VARIETY OF MEMORY AND EFFECTOR CELL TYPES. CD8(+) T CELLS CAN PERSIST FOR YEARS AND KILL TUMOUR CELLS AND VIRALLY INFECTED CELLS. THE FUNCTIONAL AND PHENOTYPIC CHANGES THAT OCCUR DURING CD8(+) T CELL DIFFERENTIATION ARE WELL CHARACTERIZED, BUT THE EPIGENETIC STATES THAT UNDERLIE THESE CHANGES ARE INCOMPLETELY UNDERSTOOD. HERE, WE REVIEW THE EPIGENETIC PROCESSES THAT DIRECT CD8(+) T CELL DIFFERENTIATION AND FUNCTION. WE FOCUS ON EPIGENETIC MODIFICATION OF DNA AND ASSOCIATED HISTONES AT GENES AND THEIR REGULATORY ELEMENTS. WE ALSO DESCRIBE STRUCTURAL CHANGES IN CHROMATIN ORGANIZATION THAT AFFECT GENE EXPRESSION. FINALLY, WE EXAMINE THE TRANSLATIONAL POTENTIAL OF EPIGENETIC INTERVENTIONS TO IMPROVE CD8(+) T CELL FUNCTION IN INDIVIDUALS WITH CHRONIC INFECTIONS AND CANCER. 2018 15 1711 39 DYSFUNCTIONAL STATE OF T CELLS OR EXHAUSTION DURING CHRONIC VIRAL INFECTIONS AND COVID-19: A REVIEW. CORONAVIRUS DISEASE 2019 (COVID-19) CONTINUOUSLY AFFECTING THE LIVES OF MILLIONS OF PEOPLE. THE VIRUS IS SPREAD THROUGH THE RESPIRATORY ROUTE TO AN UNINFECTED PERSON, CAUSING MILD-TO-MODERATE RESPIRATORY DISEASE-LIKE SYMPTOMS THAT SOMETIMES PROGRESS TO SEVERE FORM AND CAN BE FATAL. WHEN THE HOST IS INFECTED WITH THE VIRUS, BOTH INNATE AND ADAPTIVE IMMUNITY COMES INTO PLAY. THE EFFECTOR T CELLS ACT AS THE MASTER PLAYER OF ADAPTIVE IMMUNE RESPONSE IN ERADICATING THE VIRUS FROM THE SYSTEM. BUT DURING CANCER AND CHRONIC VIRAL INFECTIONS, THE FATE OF AN EFFECTOR T CELL IS ALTERED, AND THE T CELL MAY ENTERS A STATE OF EXHAUSTION, WHICH IS MARKED BY LOSS OF EFFECTOR FUNCTION, DEPLETED PROLIFERATIVE CAPACITY AND CYTOTOXIC EFFECT ACCOMPLISHED BY AN INCREASED EXPRESSION OF NUMEROUS INHIBITORY RECEPTORS SUCH AS PROGRAMMED CELL DEATH PROTEIN 1 (PD-1), LYMPHOCYTE-ACTIVATION PROTEIN 3 (LAG-3), AND CYTOTOXIC T LYMPHOCYTE-ASSOCIATED ANTIGEN 4 (CTLA-4) ON THEIR SURFACE. VARIOUS OTHER TRANSCRIPTIONAL AND EPIGENETIC CHANGES TAKE PLACE INSIDE THE T CELL WHEN IT ENTERS INTO AN EXHAUSTED STATE. LATEST STUDIES POINT TOWARD THE INDUCTION OF AN ABNORMAL IMMUNE RESPONSE SUCH AS LYMPHOPENIA, CYTOKINE STORM, AND T CELL EXHAUSTION DURING SARS-COV-2 (SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2) INFECTION. THIS REVIEW SHEDS LIGHT ON THE DYSFUNCTIONAL STATE OF T CELLS DURING CHRONIC VIRAL INFECTION AND COVID-19. UNDERSTANDING THE CAUSE AND THE EFFECT OF T CELL EXHAUSTION OBSERVED DURING COVID-19 MAY HELP RESOLVE NEW THERAPEUTIC POTENTIALS FOR TREATING CHRONIC INFECTIONS AND OTHER DISEASES. 2022 16 3538 28 IMMUNE REGULATION IN CHRONIC HEPATITIS C VIRUS INFECTION. THE IMMUNOLOGICAL RESULT OF INFECTION WITH HEPATITIS C VIRUS (HCV) DEPENDS ON THE DELICATE BALANCE BETWEEN A VIGOROUS IMMUNE RESPONSE THAT MAY CLEAR THE INFECTION, BUT WITH A RISK OF UNSPECIFIC INFLAMMATION AND, OR A LESS INFLAMMATORY RESPONSE THAT LEADS TO CHRONIC INFECTION. IN GENERAL, EXHAUSTION AND IMPAIRMENT OF CYTOTOXIC FUNCTION OF HCV-SPECIFIC T CELLS AND NK CELLS ARE FOUND IN PATIENTS WITH CHRONIC HCV INFECTION. IN CONTRAST, AN INCREASE IN IMMUNE REGULATORY FUNCTIONS IS FOUND PRIMARILY IN FORM OF INCREASED IL-10 PRODUCTION POSSIBLY DUE TO INCREASED LEVEL AND FUNCTION OF ANTI-INFLAMMATORY TREGS. THUS, THE MAJOR IMMUNE PLAYERS DURING CHRONIC HCV INFECTION ARE CHARACTERIZED BY A DECREASE OF CYTOTOXIC FUNCTION AND INCREASE OF INHIBITORY FUNCTIONS. THIS MAY BE AN APPROACH TO DIMINISH INTRAHEPATIC AND SYSTEMIC INFLAMMATION. FINALLY, THERE HAS BEEN INCREASING AWARENESS OF REGULATORY FUNCTIONS OF EPIGENETIC CHANGES IN CHRONIC HCV INFECTION. A VAST AMOUNT OF STUDIES HAVE REVEALED THE COMPLEXITY OF IMMUNE REGULATION IN CHRONIC HCV INFECTION, BUT THE INTERPLAY BETWEEN IMMUNE REGULATION IN VIRUS AND HOST REMAINS INCOMPLETELY UNDERSTOOD. THIS REVIEW PROVIDES AN OVERVIEW OF REGULATORY FUNCTIONS OF HCV-SPECIFIC T CELLS, NK CELLS, TREGS, IL-10, AND TGF-BETA, AS WELL AS EPIGENETIC CHANGES IN THE SETTING OF CHRONIC HCV INFECTION. 2016 17 2036 24 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 18 1283 25 DECIPHERING THE EPIGENETIC CODE OF T LYMPHOCYTES. THE MULTIPLE LINEAGES AND DIFFERENTIATION STATES THAT CONSTITUTE THE T-CELL COMPARTMENT ALL DERIVE FROM A COMMON THYMIC PRECURSOR. THESE DISTINCT TRANSCRIPTIONAL STATES ARE MAINTAINED BOTH IN TIME AND AFTER MULTIPLE ROUNDS OF CELL DIVISION BY THE CONCERTED ACTIONS OF A SMALL SET OF LINEAGE-DEFINING TRANSCRIPTION FACTORS THAT ACT IN CONJUNCTION WITH A SUITE OF CHROMATIN-MODIFYING ENZYMES TO ACTIVATE, REPRESS, AND FINE-TUNE GENE EXPRESSION. THESE CHROMATIN MODIFICATIONS COLLECTIVELY PROVIDE AN EPIGENETIC CODE THAT ALLOWS THE STABLE AND HERITABLE MAINTENANCE OF THE T-CELL PHENOTYPE. RECENTLY, IT HAS BECOME APPARENT THAT THE EPIGENETIC CODE REPRESENTS A THERAPEUTIC TARGET FOR A VARIETY OF IMMUNE CELL DISORDERS, INCLUDING LYMPHOMA AND ACUTE AND CHRONIC INFLAMMATORY DISEASES. HERE, WE REVIEW THE RECENT ADVANCES IN EPIGENETIC REGULATION OF GENE EXPRESSION, PARTICULARLY AS IT RELATES TO THE T-CELL DIFFERENTIATION AND FUNCTION. 2014 19 9 36 'TRAINED IMMUNITY': CONSEQUENCES FOR LYMPHOID MALIGNANCIES. IN HEMATOLOGICAL MALIGNANCIES COMPLEX INTERACTIONS EXIST BETWEEN THE IMMUNE SYSTEM, MICROORGANISMS AND MALIGNANT CELLS. ON ONE HAND, MICROORGANISMS CAN INDUCE CANCER, AS ILLUSTRATED BY SPECIFIC INFECTION-INDUCED LYMPHOPROLIFERATIVE DISEASES SUCH AS HELICOBACTER PYLORI-ASSOCIATED GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA. ON THE OTHER HAND, MALIGNANT CELLS CREATE AN IMMUNOSUPPRESSIVE ENVIRONMENT FOR THEIR OWN BENEFIT, BUT THIS ALSO RESULTS IN AN INCREASED RISK OF INFECTIONS. DISRUPTED INNATE IMMUNITY CONTRIBUTES TO THE NEOPLASTIC TRANSFORMATION OF BLOOD CELLS BY SEVERAL MECHANISMS, INCLUDING THE UNCONTROLLED CLEARANCE OF MICROBIAL AND AUTOANTIGENS RESULTING IN CHRONIC IMMUNE STIMULATION AND PROLIFERATION, CHRONIC INFLAMMATION, AND DEFECTIVE IMMUNE SURVEILLANCE AND ANTI-CANCER IMMUNITY. RESTORING DYSFUNCTION OR ENHANCING RESPONSIVENESS OF THE INNATE IMMUNE SYSTEM MIGHT THEREFORE REPRESENT A NEW ANGLE FOR THE PREVENTION AND TREATMENT OF HEMATOLOGICAL MALIGNANCIES, IN PARTICULAR LYMPHOID MALIGNANCIES AND ASSOCIATED INFECTIONS. RECENTLY, IT HAS BEEN SHOWN THAT CELLS OF THE INNATE IMMUNE SYSTEM, SUCH AS MONOCYTES/MACROPHAGES AND NATURAL KILLER CELLS, HARBOR FEATURES OF IMMUNOLOGICAL MEMORY AND DISPLAY ENHANCED FUNCTIONALITY LONG-TERM AFTER STIMULATION WITH CERTAIN MICROORGANISMS AND VACCINES. THESE FUNCTIONAL CHANGES RELY ON EPIGENETIC REPROGRAMMING AND HAVE BEEN TERMED 'TRAINED IMMUNITY'. IN THIS REVIEW THE CONCEPT OF 'TRAINED IMMUNITY' IS DISCUSSED IN THE SETTING OF LYMPHOID MALIGNANCIES. AMELIORATION OF INFECTIOUS COMPLICATIONS AND HEMATOLOGICAL DISEASE PROGRESSION CAN BE ENVISIONED TO RESULT FROM THE INDUCTION OF TRAINED IMMUNITY, BUT FUTURE STUDIES ARE REQUIRED TO PROVE THIS EXCITING NEW HYPOTHESIS. 2016 20 2399 34 EPIGENETIC REPROGRAMMING OF HOST GENES IN VIRAL AND MICROBIAL PATHOGENESIS. ONE OF THE KEY QUESTIONS IN THE STUDY OF MAMMALIAN GENE REGULATION IS HOW EPIGENETIC METHYLATION PATTERNS ON HISTONES AND DNA ARE INITIATED AND ESTABLISHED. THESE STABLE, HERITABLE, COVALENT MODIFICATIONS ARE LARGELY ASSOCIATED WITH THE REPRESSION OR SILENCING OF GENE TRANSCRIPTION, AND WHEN DEREGULATED CAN BE INVOLVED IN THE DEVELOPMENT OF HUMAN DISEASES SUCH AS CANCER. THIS ARTICLE REVIEWS EXAMPLES OF VIRUSES AND BACTERIA KNOWN OR THOUGHT TO INDUCE EPIGENETIC CHANGES IN HOST CELLS, AND HOW THIS MIGHT CONTRIBUTE TO DISEASE. THE HERITABLE NATURE OF THESE PROCESSES IN GENE REGULATION SUGGESTS THAT THEY COULD PLAY IMPORTANT ROLES IN CHRONIC DISEASES ASSOCIATED WITH MICROBIAL PERSISTENCE; THEY MIGHT ALSO EXPLAIN SO-CALLED 'HIT-AND-RUN' PHENOMENA IN INFECTIOUS DISEASE PATHOGENESIS. 2010