1  2115 103 EPIGENETIC HETEROGENEITY IN HIV-1 LATENCY ESTABLISHMENT. DESPITE PROLONGED ANTIRETROVIRAL THERAPY, HIV-1 PERSISTS AS TRANSCRIPTIONALLY INACTIVE PROVIRUSES. THE HIV-1 LATENCY REMAINS A PRINCIPAL OBSTACLE IN CURING AIDS. IT IS IMPORTANT TO UNDERSTAND MECHANISMS BY WHICH HIV-1 LATENCY IS ESTABLISHED TO MAKE THE LATENT RESERVOIR SMALLER. WE PRESENT A MOLECULAR CHARACTERIZATION OF DISTINCT POPULATIONS AT AN EARLY PHASE OF INFECTION. WE DEVELOPED AN ORIGINAL DUAL-COLOR REPORTER VIRUS TO MONITOR LTR KINETICS FROM ESTABLISHMENT TO MAINTENANCE STAGE. WE FOUND THAT THERE ARE TWO WAYS OF LATENCY ESTABLISHMENT I.E., BY IMMEDIATE SILENCING AND SLOW INACTIVATION FROM ACTIVE INFECTION. HISTONE COVALENT MODIFICATIONS, PARTICULARLY POLYCOMB REPRESSIVE COMPLEX 2 (PRC2)-MEDIATED H3K27 TRIMETHYLATION, APPEARED TO DOMINATE VIRAL TRANSCRIPTION AT THE EARLY PHASE. PRC2 ALSO CONTRIBUTES TO TIME-DEPENDENT LTR DORMANCY IN THE CHRONIC PHASE OF THE INFECTION. SIGNIFICANT DIFFERENCES IN SENSITIVITY AGAINST SEVERAL STIMULI WERE OBSERVED BETWEEN THESE TWO DISTINCT POPULATIONS. THESE RESULTS WILL EXPAND OUR UNDERSTANDING OF HETEROGENEOUS ESTABLISHMENT OF HIV-1 LATENCY POPULATIONS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
2  2109  26 EPIGENETIC FEATURES OF HIV-INDUCED T-CELL EXHAUSTION PERSIST DESPITE EARLY ANTIRETROVIRAL THERAPY. T CELL DYSFUNCTION OCCURS EARLY FOLLOWING HIV INFECTION, IMPACTING THE EMERGENCE OF NON-AIDS MORBIDITIES AND LIMITING CURATIVE EFFORTS. ART INITIATED DURING PRIMARY HIV INFECTION (PHI) CAN REVERSE THIS DYSFUNCTION, BUT THE EXTENT OF RECOVERY IS UNKNOWN. WE STUDIED 66 HIV-INFECTED INDIVIDUALS TREATED FROM EARLY PHI WITH UP TO THREE YEARS OF ART. COMPARED WITH HIV-UNINFECTED CONTROLS, CD4 AND CD8 T CELLS FROM EARLY HIV INFECTION WERE CHARACTERISED BY T CELL ACTIVATION AND INCREASED EXPRESSION OF THE IMMUNE CHECKPOINT RECEPTORS (ICRS) PD1, TIM-3 AND TIGIT. THREE YEARS OF ART LEAD TO PARTIAL - BUT NOT COMPLETE - NORMALISATION OF ICR EXPRESSION, THE DYNAMICS OF WHICH VARIED FOR INDIVIDUAL ICRS. FOR HIV-SPECIFIC CELLS, EPIGENETIC PROFILING OF TETRAMER-SORTED CD8 T CELLS REVEALED THAT EPIGENETIC FEATURES OF EXHAUSTION TYPICALLY SEEN IN CHRONIC HIV INFECTION WERE ALREADY PRESENT EARLY IN PHI, AND THAT ART INITIATION DURING PHI RESULTED IN ONLY A PARTIAL SHIFT OF THE EPIGENOME TO ONE WITH MORE FAVOURABLE MEMORY CHARACTERISTICS. THESE FINDINGS SUGGEST THAT ALTHOUGH ART INITIATION DURING PHI RESULTS IN SIGNIFICANT IMMUNE RECONSTITUTION, THERE MAY BE ONLY PARTIAL RESOLUTION OF HIV-RELATED PHENOTYPIC AND EPIGENETIC CHANGES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  1239  31 CURE AND LONG-TERM REMISSION STRATEGIES. THE MAJORITY OF VIRALLY SUPPRESSED INDIVIDUALS WILL EXPERIENCE RAPID VIRAL REBOUND UPON ANTIRETROVIRAL THERAPY (ART) INTERRUPTION, PROVIDING A STRONG RATIONALE FOR THE DEVELOPMENT OF CURE STRATEGIES. MOREOVER, DESPITE ART VIROLOGICAL CONTROL, HIV INFECTION IS STILL ASSOCIATED WITH CHRONIC IMMUNE ACTIVATION, INFLAMMATION, COMORBIDITIES, AND ACCELERATED AGING. THESE EFFECTS ARE BELIEVED TO BE DUE, IN PART, TO LOW-GRADE PERSISTENT TRANSCRIPTION AND TRICKLING PRODUCTION OF VIRAL PROTEINS FROM THE POOL OF LATENT PROVIRUSES CONSTITUTING THE VIRAL RESERVOIR. IN RECENT YEARS THERE HAS BEEN AN INCREASING INTEREST IN DEVELOPING WHAT HAS BEEN TERMED A FUNCTIONAL CURE FOR HIV. THIS APPROACH ENTAILS THE LONG-TERM, DURABLE CONTROL OF VIRAL EXPRESSION IN THE ABSENCE OF THERAPY, PREVENTING DISEASE PROGRESSION AND TRANSMISSION, DESPITE THE PRESENCE OF DETECTABLE INTEGRATED PROVIRUSES. ONE SUCH STRATEGY, THE BLOCK-AND-LOCK APPROACH FOR A FUNCTIONAL CURE, PROPOSES THE EPIGENETIC SILENCING OF PROVIRAL EXPRESSION, LOCKING THE VIRUS IN A PROFOUND LATENT STATE, FROM WHICH REACTIVATION IS VERY UNLIKELY. THE PROOF-OF-CONCEPT FOR THIS APPROACH WAS DEMONSTRATED WITH THE USE OF A SPECIFIC SMALL MOLECULE TARGETING HIV TRANSCRIPTION. HERE WE REVIEW THE PRINCIPLES BEHIND THE BLOCK-AND-LOCK APPROACH AND SOME OF THE ADDITIONAL STRATEGIES PROPOSED TO SILENCE HIV EXPRESSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  2143  36 EPIGENETIC LANDSCAPE OF HIV-1 INFECTION IN PRIMARY HUMAN MACROPHAGE. HUMAN IMMUNODEFICIENCY VIRUS (HIV)-INFECTED MACROPHAGES ARE LONG-LIVED CELLS THAT SUSTAIN PERSISTENT VIRUS EXPRESSION, WHICH IS BOTH A BARRIER TO VIRAL ERADICATION AND CONTRIBUTOR TO NEUROLOGICAL COMPLICATIONS IN PATIENTS DESPITE ANTIRETROVIRAL THERAPY (ART). TO BETTER UNDERSTAND THE REGULATION OF HIV-1 IN MACROPHAGES, WE COMPARED HIV-INFECTED PRIMARY HUMAN MONOCYTE-DERIVED MACROPHAGES (MDM) TO ACUTELY INFECTED PRIMARY CD4 T CELLS AND JURKAT CELLS LATENTLY INFECTED WITH HIV (JLAT 8.4). HIV GENOMES IN MDM WERE ACTIVELY TRANSCRIBED DESPITE ENRICHMENT WITH HETEROCHROMATIN-ASSOCIATED H3K9ME3 ACROSS THE COMPLETE HIV GENOME IN COMBINATION WITH ELEVATED ACTIVATION MARKS OF H3K9AC AND H3K27AC AT THE LONG TERMINAL REPEAT (LTR). MACROPHAGE PATTERNS CONTRASTED WITH JLAT CELLS, WHICH SHOWED CONVENTIONAL BIVALENT H3K4ME3/H3K27ME3, AND ACUTELY INFECTED CD4 T CELLS, WHICH SHOWED AN INTERMEDIATE EPIGENOTYPE. 5'-METHYLCYTOSINE (5MC) WAS ENRICHED ACROSS THE HIV GENOME IN LATENTLY INFECTED JLAT CELLS, WHILE 5'-HYDROXYMETHYLCYTOSINE (5HMC) WAS ENRICHED IN CD4 CELLS AND MDMS. HIV INFECTION INDUCED MULTINUCLEATION OF MDMS ALONG WITH DNA DAMAGE-ASSOCIATED P53 PHOSPHORYLATION, AS WELL AS LOSS OF TET2 AND THE NUCLEAR REDISTRIBUTION OF 5-HYDOXYMETHYLATION. TAKEN TOGETHER, OUR FINDINGS SUGGEST THAT HIV INDUCES A UNIQUE MACROPHAGE NUCLEAR AND TRANSCRIPTIONAL PROFILE, AND VIRAL GENOMES ARE MAINTAINED IN A NONCANONICAL BIVALENT EPIGENETIC STATE. IMPORTANCE MACROPHAGES SERVE AS A RESERVOIR FOR LONG-TERM PERSISTENCE AND CHRONIC PRODUCTION OF HIV. WE FOUND AN ATYPICAL EPIGENETIC CONTROL OF HIV IN MACROPHAGES MARKED BY HETEROCHROMATIC H3K9ME3 DESPITE ACTIVE VIRAL TRANSCRIPTION. HIV INFECTION INDUCED CHANGES IN MACROPHAGE NUCLEAR MORPHOLOGY AND EPIGENETIC REGULATORY FACTORS. THESE FINDINGS MAY IDENTIFY NEW MECHANISMS TO CONTROL CHRONIC HIV EXPRESSION IN INFECTED MACROPHAGES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5    64  36 A HIGH-THROUGHPUT SCREENING ASSAY FOR SILENCING ESTABLISHED HIV-1 MACROPHAGE INFECTION IDENTIFIES NUCLEOSIDE ANALOGS THAT PERTURB H3K9ME3 ON PROVIRAL GENOMES. HIV-INFECTED MACROPHAGES ARE LONG-LIVED CELLS THAT REPRESENT A BARRIER TO FUNCTIONAL CURE. ADDITIONALLY, LOW-LEVEL VIRAL EXPRESSION BY CENTRAL NERVOUS SYSTEM (CNS) MACROPHAGES CONTRIBUTES TO NEUROCOGNITIVE DEFICITS THAT DEVELOP DESPITE ANTIRETROVIRAL THERAPY (ART). WE RECENTLY IDENTIFIED H3K9ME3 AS AN ATYPICAL EPIGENETIC MARK ASSOCIATED WITH CHRONIC HIV INFECTION IN MACROPHAGES. THUS, STRATEGIES ARE NEEDED TO SUPPRESS HIV-1 EXPRESSION IN MACROPHAGES, BUT THE UNIQUE MYELOID ENVIRONMENT AND THE RESPONSIBLE MACROPHAGE/CNS-TROPIC STRAINS REQUIRE CELL/STRAIN-SPECIFIC APPROACHES. HERE, WE GENERATED AN HIV-1 REPORTER VIRUS FROM A CNS-DERIVED STRAIN WITH INTACT AUXILIARY GENES EXPRESSING DESTABILIZED LUCIFERASE. WE EMPLOYED THIS REPORTER VIRUS IN POLYCLONAL INFECTION OF PRIMARY HUMAN MONOCYTE-DERIVED MACROPHAGES (MDM) FOR A HIGH-THROUGHPUT SCREEN (HTS) TO IDENTIFY COMPOUNDS THAT SUPPRESS VIRUS EXPRESSION FROM ESTABLISHED MACROPHAGE INFECTION. SCREENING ~6,000 KNOWN DRUGS AND COMPOUNDS YIELDED 214 HITS. A SECONDARY SCREEN WITH 10-DOSE TITRATION IDENTIFIED 24 MEETING CRITERIA FOR HIV-SELECTIVE ACTIVITY. USING THREE REPLICATION-COMPETENT CNS-DERIVED MACROPHAGE-TROPIC HIV-1 ISOLATES AND VIRAL GENE EXPRESSION READOUT IN MDM, WE CONFIRMED THE EFFECT OF THREE PURINE ANALOGS, NELARABINE, FLUDARABINE, AND ENTECAVIR, SHOWING THE SUPPRESSION OF HIV-1 EXPRESSION FROM ESTABLISHED MACROPHAGE INFECTION. NELARABINE INHIBITED THE FORMATION OF H3K9ME3 ON HIV GENOMES IN MACROPHAGES. THUS, THIS NOVEL HTS ASSAY CAN IDENTIFY SUPPRESSORS OF HIV-1 TRANSCRIPTION IN ESTABLISHED MACROPHAGE INFECTION, SUCH AS NUCLEOSIDE ANALOGS AND HDAC INHIBITORS, WHICH MAY BE LINKED TO H3K9ME3 MODIFICATION. THIS SCREEN MAY BE USEFUL TO IDENTIFY NEW METABOLIC AND EPIGENETIC AGENTS THAT AMELIORATE HIV-DRIVEN NEUROINFLAMMATION IN PEOPLE ON ART OR PREVENT VIRAL RECRUDESCENCE FROM MACROPHAGE RESERVOIRS IN STRATEGIES TO ACHIEVE ART-FREE REMISSION. IMPORTANCE MACROPHAGES INFECTED BY HIV-1 ARE A LONG-LIVED RESERVOIR AND A BARRIER IN CURRENT EFFORTS TO ACHIEVE HIV CURE AND ALSO CONTRIBUTE TO NEUROCOGNITIVE COMPLICATIONS IN PEOPLE DESPITE ANTIRETROVIRAL THERAPY (ART). SILENCING HIV EXPRESSION IN THESE CELLS WOULD BE OF GREAT VALUE, BUT THE REGULATION OF HIV-1 IN MACROPHAGES DIFFERS FROM T CELLS. WE DEVELOPED A NOVEL HIGH-THROUGHPUT SCREEN FOR COMPOUNDS THAT CAN SILENCE ESTABLISHED INFECTION OF PRIMARY MACROPHAGES, AND IDENTIFIED AGENTS THAT DOWNREGULATE VIRUS EXPRESSION AND ALTER PROVIRUS EPIGENETIC PROFILES. THE SIGNIFICANCE OF THIS ASSAY IS THE POTENTIAL TO IDENTIFY NEW DRUGS THAT ACT IN THE UNIQUE MACROPHAGE ENVIRONMENT ON RELEVANT VIRAL STRAINS, WHICH MAY CONTRIBUTE TO ADJUNCTIVE TREATMENT FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS AND/OR PREVENT VIRAL REBOUND IN EFFORTS TO ACHIEVE ART-FREE REMISSION OR CURE.	2023	
                                                                                    
6  5094  25 PLASMA EXTRACELLULAR VESICLE SUBTYPES MAY BE USEFUL AS POTENTIAL BIOMARKERS OF IMMUNE ACTIVATION IN PEOPLE WITH HIV. BACKGROUND: EXTRACELLULAR VESICLES (EVS) ARE INTERCELLULAR MESSENGERS WITH EPIGENETIC POTENTIAL SINCE THEY CAN SHUTTLE MICRORNA (MIRNA). EVS AND MIRNA PLAY A ROLE IN HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION IMMUNOPATHOGENESIS. CHRONIC IMMUNE ACTIVATION AND SYSTEMIC INFLAMMATION DURING HIV INFECTION DESPITE EFFECTIVE ANTIRETROVIRAL THERAPY (ART) ARE ASSOCIATED WITH NON-ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) COMORBIDITIES IN PEOPLE LIVING WITH HIV (PLWH). ANALYSIS OF PLASMA EVS AND THEIR MIRNA CONTENT MAY BE USEFUL AS IMMUNE ACTIVATION OR INFLAMMATORY BIOMARKERS IN PLWH RECEIVING ART. IN THIS STUDY, WE HYPOTHESIZED THAT THE NUMBER, SIZE, AND MIRNA OF LARGE AND SMALL EVS COULD REFLECT IMMUNE ACTIVATION ASSOCIATED WITH AN ELEVATED CD8 T-CELL COUNT OR A LOW CD4/CD8 RATIO IN PLWH. METHODS: PLASMA EVS SUBTYPE PURIFIED FROM PLWH AND UNINFECTED CONTROLS WERE SIZED USING DYNAMIC LIGHT SCATTERING AND QUANTIFIED USING FLOW CYTOMETRY AND ACETYLCHOLINE ESTERASE (ACHE) ACTIVITY. EXPRESSION OF MATURE MIRNAS MIR-92, MIR-155, MIR-223 WAS MEASURED BY QUANTITATIVE REVERSE-TRANSCRIPTASE POLYMERASE CHAIN REACTION IN EVS AND LEUCOCYTES. RESULTS: HIV INFECTION INDUCES INCREASED PRODUCTION OF SMALL EVS IN PLASMA. EV SUBTYPES WERE DIFFERENTIALLY ENRICHED IN MIR-92, MIR-155, AND MIR-223. POSITIVE CORRELATIONS BETWEEN CD8 T-CELL COUNT AND LARGE EVS ABUNDANCE AND SMALL EVS ACHE ACTIVITY WERE OBSERVED. CD4/CD8 RATIO WAS NEGATIVELY CORRELATED WITH SMALL EV ACHE ACTIVITY, AND MIRNA-155 LEVEL PER SMALL EV WAS NEGATIVELY CORRELATED WITH CD8 T-CELL COUNT. CONCLUSIONS: THESE FINDINGS SUGGEST THAT QUANTIFYING LARGE OR SMALL EVS AND PROFILING MIRNA CONTENT PER EV MIGHT PROVIDE NEW FUNCTIONAL BIOMARKERS OF IMMUNE ACTIVATION AND INFLAMMATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  4849  19 OPIOID-MEDIATED HIV-1 IMMUNOPATHOGENESIS. DESPITE THE ABILITY OF COMBINATION ANTIRETROVIRAL THERAPY TO DRAMATICALLY SUPPRESS VIREMIA, THE BRAIN CONTINUES TO BE A RESERVOIR OF HIV-1 LOW-LEVEL REPLICATION. ADDING FURTHER COMPLEXITY TO THIS IS THE COMORBIDITY OF DRUG ABUSE WITH HIV-1 ASSOCIATED NEUROCOGNITIVE DISORDERS AND NEUROHIV. AMONG SEVERAL ABUSED DRUGS, THE USE OF OPIATES IS HIGHLY PREVALENT IN HIV-1 INFECTED INDIVIDUALS, BOTH AS AN ABUSED DRUG AS WELL AS FOR PAIN MANAGEMENT. OPIOIDS AND THEIR RECEPTORS HAVE ATTAINED NOTABLE ATTENTION OWING TO THEIR ABILITY TO MODULATE IMMUNE FUNCTIONS, IN TURN, IMPACTING DISEASE PROGRESSION. VARIOUS CELL CULTURE, ANIMAL AND HUMAN STUDIES HAVE IMPLICATED THE ROLE OF OPIOIDS AND THEIR RECEPTORS IN MODULATING VIRAL REPLICATION AND VIRUS-MEDIATED PATHOLOGY BOTH POSITIVELY AND NEGATIVELY. FURTHER, THE COMBINATORIAL EFFECTS OF HIV-1/HIV-1 PROTEINS AND MORPHINE HAVE DEMONSTRATED ACTIVATION OF INFLAMMATORY SIGNALING IN THE HOST SYSTEM. HEREIN, WE SUMMARIZED THE CURRENT KNOWLEDGE ON THE ROLE OF OPIOIDS ON PERIPHERAL IMMUNOPATHOGENESIS, VIRAL IMMUNOPATHOGENESIS, EPIGENETIC PROFILES OF THE HOST AND VIRAL GENOME, NEUROPATHOGENESIS OF SIV/SHIV-INFECTED NON-HUMAN PRIMATES, BLOOD-BRAIN-BARRIER, HIV-1 VIRAL LATENCY, AND VIRAL REBOUND. OVERALL, THIS REVIEW PROVIDES RECENT INSIGHTS INTO THE ROLE OF OPIOIDS IN HIV-1 IMMUNOPATHOGENESIS. GRAPHICAL ABSTRACT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8  6435  31 THE XPB SUBUNIT OF THE TFIIH COMPLEX PLAYS A CRITICAL ROLE IN HIV-1 TRANSCRIPTION AND XPB INHIBITION BY SPIRONOLACTONE PREVENTS HIV-1 REACTIVATION FROM LATENCY. HIV TRANSCRIPTION REQUIRES ASSEMBLY OF CELLULAR TRANSCRIPTION FACTORS AT THE HIV-1PROMOTER. THE TFIIH GENERAL TRANSCRIPTION FACTOR FACILITATES TRANSCRIPTION INITIATION BY OPENING THE DNA STRANDS AROUND THE TRANSCRIPTION START SITE AND PHOSPHORYLATING THE C-TERMINAL DOMAIN FOR RNA POLYMERASE II (RNAPII) FOR ACTIVATION. SPIRONOLACTONE (SP), AN FDA APPROVED ALDOSTERONE ANTAGONIST, TRIGGERS THE PROTEASOMAL DEGRADATION OF THE XPB SUBUNIT OF TFIIH, AND CONCURRENTLY SUPPRESSES ACUTE HIV INFECTION IN VITRO HERE WE INVESTIGATED SP AS A POSSIBLE BLOCK-AND-LOCK AGENT FOR A FUNCTIONAL CURE AIMED AT THE TRANSCRIPTIONAL SILENCING OF THE VIRAL RESERVOIR. THE LONG-TERM ACTIVITY OF SP WAS INVESTIGATED IN PRIMARY AND CELL LINE MODELS OF HIV-1 LATENCY AND REACTIVATION. WE SHOW THAT SP RAPIDLY INHIBITS HIV-1 TRANSCRIPTION BY REDUCING RNAPII RECRUITMENT TO THE HIV-1 GENOME. SHRNA KNOCKDOWN OF XPB CONFIRMED XPB DEGRADATION AS THE MECHANISM OF ACTION. UNFORTUNATELY, LONG-TERM PRE-TREATMENT WITH SP DOES NOT RESULT IN EPIGENETIC SUPPRESSION OF HIV UPON SP TREATMENT INTERRUPTION, SINCE VIRUS RAPIDLY REBOUNDS WHEN XPB REEMERGES; HOWEVER, SP ALONE WITHOUT ART MAINTAINS THE TRANSCRIPTIONAL SUPPRESSION. IMPORTANTLY, SP INHIBITS HIV REACTIVATION FROM LATENCY IN BOTH CELL LINE MODELS AND RESTING CD4(+)T CELLS ISOLATED FROM AVIREMIC INFECTED INDIVIDUALS UPON CELL STIMULATION WITH LATENCY REVERSING AGENTS. FURTHERMORE, LONG-TERM TREATMENT WITH CONCENTRATIONS OF SP THAT POTENTLY DEGRADE XPB DOES NOT LEAD TO GLOBAL DYSREGULATION OF CELLULAR MRNA EXPRESSION. OVERALL, THESE RESULTS SUGGEST THAT XPB PLAYS A KEY ROLE IN HIV TRANSCRIPTIONAL REGULATION AND XPB DEGRADATION BY SP STRENGTHENS THE POTENTIAL OF HIV TRANSCRIPTIONAL INHIBITORS IN BLOCK-AND-LOCK HIV CURE APPROACHES.IMPORTANCE ANTIRETROVIRAL THERAPY (ART) EFFECTIVELY REDUCES AN INDIVIDUAL'S HIV LOADS TO BELOW THE DETECTION LIMIT, NEVERTHELESS RAPID VIRAL REBOUND IMMEDIATELY ENSUES UPON TREATMENT INTERRUPTION. FURTHERMORE, VIRALLY SUPPRESSED INDIVIDUALS EXPERIENCE CHRONIC IMMUNE ACTIVATION FROM ONGOING LOW-LEVEL VIRUS EXPRESSION. THUS, THE IMPORTANCE OF IDENTIFYING NOVEL THERAPEUTICS TO EXPLORE IN BLOCK-AND-LOCK HIV FUNCTIONAL CURE APPROACHES, AIMED AT THE TRANSCRIPTIONAL AND EPIGENETIC SILENCING OF THE VIRAL RESERVOIR TO BLOCK REACTIVATION FROM LATENCY. WE INVESTIGATED THE POTENTIAL OF REPURPOSING THE FDA-APPROVED SPIRONOLACTONE (SP), AS ONE SUCH DRUG. SP TREATMENT RAPIDLY DEGRADES A HOST TRANSCRIPTION FACTOR SUBUNIT, XPB, INHIBITING HIV TRANSCRIPTION AND BLOCKING REACTIVATION FROM LATENCY. LONG-TERM SP TREATMENT DOES NOT AFFECT CELLULAR VIABILITY, CELL CYCLE PROGRESSION OR GLOBAL CELLULAR TRANSCRIPTION. SP ALONE BLOCKS HIV TRANSCRIPTION IN THE ABSENCE OF ART BUT DOES NOT DELAY REBOUND UPON DRUG REMOVAL AS XPB RAPIDLY REEMERGES. THIS STUDY HIGHLIGHTS XPB AS A NOVEL DRUG TARGET IN BLOCK-AND-LOCK THERAPEUTIC APPROACHES.	2021	

9  3555  25 IMPACT OF AGE, ANTIRETROVIRAL THERAPY, AND CANCER ON EPIGENETIC AGING IN PEOPLE LIVING WITH HIV. BACKGROUND: PREMATURE AGING HAS BEEN IDENTIFIED AS A GLOBAL RISK FACTOR FOR CANCER. CAUSES OF PREMATURE AGING ARE MULTIFACTORIAL, INCLUDING INFLAMMATION, INFECTION, CHRONIC STRESS, AND LIFESTYLE FACTORS. METHOD: WE EVALUATED WHETHER PREMATURE AGING IN PEOPLE LIVING WITH HIV (PLWH) WAS ASSOCIATED WITH ANTIRETROVIRAL THERAPY (ART) OR THE DIAGNOSIS OF CANCER. WE USED WELL-ESTABLISHED DNA METHYLATION PATTERNS TO ASSESS PREMATURE AGING, USING HORVATH ET AL., IN INDIVIDUALS WITH HIV LOCATED IN CLEVELAND, OHIO AND COMPARED THESE TO STANDARDIZED DATASETS OF US HISTORICAL BLOOD SAMPLES. SOME OF THE PLWH DEVELOPED CANCER OVER TIME. RESULTS: WE FOUND THAT DNA METHYLATION ANALYSIS IDENTIFIED ACCELERATED AGING IN PLWH WHEREAS ART THERAPY MITIGATED THE ADVANCEMENT OF DNA METHYLATION AGE. A VARIETY OF CANCERS WERE OBSERVED IN THIS POPULATION, BUT A CANCER DIAGNOSIS WAS NOT SIGNIFICANTLY ASSOCIATED WITH MORE ADVANCED DNA METHYLATION AGE. CONCLUSION: WE FIND THAT THE AGE ACCELERATION DETECTED IN PLWH IS MITIGATED BY ART THERAPY AND IS NOT FURTHER ACCELERATED BY A DIAGNOSIS OF CANCER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10   284  21 AGEING WITH HIV: CHALLENGES AND BIOMARKERS. THE ANTIRETROVIRAL TREATMENT (ART) DEVELOPED TO CONTROL HIV INFECTION LED TO A REVOLUTION IN THE PROGNOSIS OF PEOPLE LIVING WITH HIV (PLWH). PLWH UNDERWENT FROM SUFFERING SEVERE DISEASE AND OFTEN FATAL COMPLICATIONS AT YOUNG AGES TO HAVING A CHRONIC CONDITION AND A LIFE EXPECTANCY CLOSE TO THE GENERAL POPULATION. NEVERTHELESS, CHRONIC AGE-RELATED DISEASES INCREASE AS PLWH AGE. THE HARMFUL EFFECT OF HIV INFECTION ON THE INDIVIDUAL'S IMMUNE SYSTEM ADDS TO ITS DETERIORATION DURING AGEING, EXACERBATING COMORBIDITIES. IN ADDITION, PLWH ARE MORE EXPOSED TO RISK FACTORS AFFECTING AGEING, SUCH AS COINFECTIONS OR HARMFUL LIFESTYLES. THE ART INITIATION REVERSES THE BIOLOGICAL AGEING PROCESS BUT ONLY PARTIALLY, AND ADDITIONALLY CAN HAVE SOME TOXICITIES THAT INFLUENCE AGEING. OBSERVATIONAL STUDIES SUGGEST PREMATURE AGEING IN PLWH. THEREFORE, THERE IS CONSIDERABLE INTEREST IN THE EARLY PREDICTION OF UNHEALTHY AGEING THROUGH VALIDATED BIOMARKERS, EASY TO IMPLEMENT IN HIV-CLINICAL SETTINGS. THE MOST PROMISING BIOMARKERS ARE SECOND-GENERATION EPIGENETIC CLOCKS AND INTEGRATIVE ALGORITHMS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
11  4818  21 OCCURRENCE OF ACCELERATED EPIGENETIC AGING AND METHYLATION DISRUPTIONS IN HUMAN IMMUNODEFICIENCY VIRUS INFECTION BEFORE ANTIRETROVIRAL THERAPY. BACKGROUND: WHETHER ACCELERATED AGING DEVELOPS OVER THE COURSE OF CHRONIC HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION OR CAN BE OBSERVED BEFORE SIGNIFICANT IMMUNOSUPPRESSION ON IS UNKNOWN. WE STUDIED DNA METHYLATION IN BLOOD TO ESTIMATE CELLULAR AGING IN PERSONS LIVING WITH HIV (PLWH) BEFORE THE INITIATION OF ANTIRETROVIRAL THERAPY (ART). METHODS: A TOTAL OF 378 ART-NAIVE PLWH WHO HAD CD4 T-CELL COUNTS >500/MICROL AND WERE ENROLLED IN THE STRATEGIC TIMING OF ANTIRETROVIRAL THERAPY TRIAL (PULMONARY SUBSTUDY) WERE COMPARED WITH 34 HIV-NEGATIVE CONTROLS. DNA METHYLATION WAS PERFORMED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND DIFFERENTIALLY METHYLATED REGIONS (DMRS) IN PLWH COMPARED WITH CONTROLS WERE IDENTIFIED USING A ROBUST LINEAR MODEL. METHYLATION AGE WAS CALCULATED USING A PREVIOUSLY DESCRIBED EPIGENETIC CLOCK. RESULTS: THERE WERE A TOTAL OF 56 639 DMPS AND 6103 DMRS AT A FALSE DISCOVERY RATE OF <0.1. THE TOP 5 DMPS CORRESPONDED TO GENES NLRC5, VRK2, B2M, AND GPR6 AND WERE HIGHLY ENRICHED FOR CANCER-RELATED PATHWAYS. PLWH HAD SIGNIFICANTLY HIGHER METHYLATION AGE THAN HIV-NEGATIVE CONTROLS (P = .001), WITH BLACK RACE, LOW CD4 AND HIGH CD8 T-CELL COUNTS, AND DURATION OF HIV BEING RISK FACTORS FOR AGE ACCELERATION. CONCLUSIONS: PLWH BEFORE THE INITIATION OF ART AND WITH PRESERVED IMMUNE STATUS SHOW EVIDENCE OF ADVANCED METHYLATION AGING.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12   492  27 ASSESSMENT OF HIV-1 INTEGRATION IN TISSUES AND SUBSETS ACROSS INFECTION STAGES. THE INTEGRATION OF HIV DNA INTO THE HOST GENOME CONTRIBUTES TO LIFELONG INFECTION IN MOST INDIVIDUALS. FEW STUDIES HAVE EXAMINED INTEGRATION IN LYMPHOID TISSUE, WHERE HIV PREDOMINANTLY PERSISTS BEFORE AND AFTER ANTIRETROVIRAL TREATMENT (ART). OF PARTICULAR INTEREST IS WHETHER INTEGRATION SITE DISTRIBUTIONS DIFFER BETWEEN INFECTION STAGES WITH PAIRED BLOOD AND TISSUE COMPARISONS. HERE, WE PROFILED HIV INTEGRATION SITE DISTRIBUTIONS IN SORTED MEMORY, TISSUE-RESIDENT, AND/OR FOLLICULAR HELPER CD4+ T CELL SUBSETS FROM PAIRED BLOOD AND LYMPHOID TISSUE SAMPLES FROM ACUTE, CHRONIC, AND ART-TREATED INDIVIDUALS. WE OBSERVED MINOR DIFFERENCES IN THE FREQUENCY OF NONINTRONIC AND NONDISTAL INTERGENIC SITES, VARYING WITH TISSUE AND RESIDENCY PHENOTYPES DURING ART. GENOMIC AND EPIGENETIC ANNOTATIONS WERE GENERALLY SIMILAR. CLONAL EXPANSION OF CELLS MARKED BY IDENTICAL INTEGRATION SITES WAS DETECTED, WITH INCREASED DETECTION IN CHRONIC AND ART-TREATED INDIVIDUALS. HOWEVER, OVERLAP BETWEEN OR WITHIN CD4+ T CELL SUBSETS OR TISSUE COMPARTMENTS WAS ONLY OBSERVED IN 8 UNIQUE SITES OF THE 3540 SITES STUDIED. TOGETHER, THESE FINDINGS SUGGEST THAT SHARED INTEGRATION SITES BETWEEN BLOOD AND TISSUE MAY, DEPENDING ON THE TISSUE SITE, BE THE EXCEPTION RATHER THAN THE RULE AND INDICATE THAT ADDITIONAL STUDIES ARE NECESSARY TO FULLY UNDERSTAND THE HETEROGENEITY OF TISSUE-SEQUESTERED HIV RESERVOIRS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13  1703  21 DYNAMICS AND EPIGENETIC SIGNATURE OF REGULATORY T-CELLS FOLLOWING ANTIRETROVIRAL THERAPY INITIATION IN ACUTE HIV INFECTION. BACKGROUND: HIV INFECTION PROMOTES THE EXPANSION OF IMMUNOSUPPRESSIVE REGULATORY T-CELLS (TREGS), CONTRIBUTING TO IMMUNE DYSFUNCTION, TISSUE FIBROSIS AND DISEASE PROGRESSION. EARLY ANTIRETROVIRAL TREATMENT (ART) UPON HIV INFECTION IMPROVES CD4 COUNT AND DECREASES IMMUNE ACTIVATION. HOWEVER, TREG DYNAMICS AND THEIR EPIGENETIC REGULATION FOLLOWING EARLY ART INITIATION REMAIN UNDERSTUDIED. METHODS: TREG SUBSETS WERE CHARACTERIZED BY FLOW CYTOMETRY IN 103 INDIVIDUALS, INCLUDING UNTREATED HIV-INFECTED PARTICIPANTS IN ACUTE AND CHRONIC PHASES, ART-TREATED IN EARLY INFECTION, ELITE CONTROLLERS (ECS), IMMUNOLOGICAL CONTROLLERS (ICS), AND HIV-UNINFECTED CONTROLS. THE METHYLATION STATUS OF SIX REGULATORY REGIONS OF THE FOXP3 GENE WAS ASSESSED USING MISEQ TECHNOLOGY. FINDINGS: TOTAL TREG FREQUENCY INCREASED OVERTIME DURING HIV INFECTION, WHICH WAS NORMALIZED IN EARLY ART RECIPIENTS. TREGS IN UNTREATED INDIVIDUALS EXPRESSED HIGHER LEVELS OF ACTIVATION AND IMMUNOSUPPRESSIVE MARKERS (CD39, AND LAP(TGF-BETA1)), WHICH REMAINED UNCHANGED FOLLOWING EARLY ART. EXPRESSION OF GUT MIGRATION MARKERS (CCR9, INTEGRIN-BETA7) BY TREGS WAS ELEVATED DURING UNTREATED HIV INFECTION, WHILE THEY DECLINED WITH THE DURATION OF ART BUT NOT UPON EARLY ART INITIATION. NOTABLY, GUT-HOMING TREGS EXPRESSING LAP(TGF-BETA1) AND CD39 REMAINED HIGHER DESPITE EARLY TREATMENT. ADDITIONALLY, THE INCREASE IN LAP(TGF-BETA1)(+) TREGS OVERTIME WERE CONSISTENT WITH HIGHER DEMETHYLATION OF CONSERVED NON-CODING SEQUENCE (CNS)-1 IN THE FOXP3 GENE. REMARKABLY, LAP(TGF-BETA1)-EXPRESSING TREGS IN ECS WERE SIGNIFICANTLY HIGHER THAN IN UNINFECTED SUBJECTS, WHILE THE MARKERS OF TREG ACTIVATION AND GUT MIGRATION WERE NOT DIFFERENT. INTERPRETATION: EARLY ART INITIATION WAS UNABLE TO CONTROL THE LEVELS OF IMMUNOSUPPRESSIVE TREG SUBSETS AND THEIR GUT MIGRATION POTENTIAL, WHICH COULD ULTIMATELY CONTRIBUTE TO GUT TISSUE FIBROSIS AND HIV DISEASE PROGRESSION. FUNDING: THIS STUDY WAS FUNDED BY THE CANADIAN INSTITUTES OF HEALTH RESEARCH (CIHR, GRANT MOP 142294) AND IN PART BY THE AIDS AND INFECTIOUS DISEASES NETWORK OF THE RESEAU SIDA ET MALADIES INFECTIEUSES DU FONDS DE RECHERCHE DU QUEBEC-SANTE (FRQ-S).	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  4596  29 NATURAL KILLER CELLS IN HUMAN IMMUNODEFICIENCY VIRUS-1 INFECTION: SPOTLIGHT ON THE IMPACT OF HUMAN CYTOMEGALOVIRUS. HUMAN CYTOMEGALOVIRUS (HCMV) HAS BEEN CLOSELY ASSOCIATED WITH THE HUMAN RACE ACROSS EVOLUTIONARY TIME. HCMV CO-INFECTION IS NEARLY UNIVERSAL IN HUMAN IMMUNODEFICIENCY VIRUS-1 (HIV-1)-INFECTED INDIVIDUALS AND REMAINS AN IMPORTANT COFACTOR IN HIV-1 DISEASE PROGRESSION EVEN IN THE ERA OF EFFECTIVE ANTIRETROVIRAL TREATMENT. HCMV INFECTION HAS BEEN SHOWN TO HAVE A BROAD AND POTENT INFLUENCE ON THE HUMAN IMMUNE SYSTEM AND HAS BEEN LINKED WITH THE DISCOVERY AND CHARACTERIZATION OF ADAPTIVE NATURAL KILLER (NK) CELLS. DISTINCT NK-CELL SUBSETS, PREDOMINATELY EXPRESSING THE ACTIVATING RECEPTOR NKG2C AND THE MARKER OF TERMINAL DIFFERENTIATION CD57, EXPAND IN RESPONSE TO HCMV. THESE NK-CELL POPULATIONS ENGAGED IN THE LONG-LASTING INTERACTION WITH HCMV, IN ADDITION TO CHARACTERISTIC BUT VARIABLE EXPRESSION OF SURFACE RECEPTORS, EXHIBIT REDUCED EXPRESSION OF SIGNALING PROTEINS AND TRANSCRIPTION FACTORS EXPRESSED BY CANONICAL NK CELLS. BROAD EPIGENETIC MODIFICATIONS DRIVE THE EMERGENCE AND PERSISTENCE OF HCMV-ADAPTED NK CELLS THAT HAVE DISTINCT FUNCTIONAL CHARACTERISTICS. NKG2C(+) NK-CELL EXPANSIONS HAVE BEEN OBSERVED IN HIV-1 INFECTED PATIENTS AND OTHER ACUTE AND CHRONIC VIRAL INFECTIONS BEING SYSTEMATICALLY ASSOCIATED WITH HCMV SEROPOSITIVITY. THE LATTER IS POTENTIALLY AN IMPORTANT CONFOUNDING VARIABLE IN STUDIES FOCUSED ON THE CELLULAR NK-CELL RECEPTOR REPERTOIRE AND FUNCTIONAL CAPACITY. HERE, FOCUSING ON HIV-1 INFECTION WE REVIEW THE EVIDENCE IN FAVOR OF "ADAPTIVE" CHANGES LIKELY INDUCED BY HCMV CO-INFECTION IN NK-CELL SUBSETS. WE HIGHLIGHT A NUMBER OF KEY QUESTIONS AND HOW INSIGHTS INTO THE ADAPTIVE BEHAVIOR OF NK CELLS WILL INFORM NEW STRATEGIES EXPLOITING THEIR UNIQUE PROPERTIES IN THE FIGHT AGAINST HIV-1.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15  3938  23 LNC(ING)RNAS TO THE "SHOCK AND KILL" STRATEGY FOR HIV-1 CURE. THE ADVENT OF ANTIRETROVIRAL THERAPY ALMOST 25 YEARS AGO HAS TRANSFORMED HIV-1 INFECTION INTO A MANAGEABLE CHRONIC CONDITION, ALBEIT STILL INCURABLE. THE INABILITY OF THE TREATMENT REGIMEN TO ELIMINATE LATENTLY INFECTED CELLS THAT HARBOR THE VIRUS IN AN EPIGENETICALLY SILENT STATE POSES A MAJOR HURDLE. CURRENT CURE APPROACHES ARE FOCUSED ON A "SHOCK AND KILL" STRATEGY THAT USES LATENCY-REVERSING AGENTS TO CHEMICALLY REVERSE THE PROVIRAL QUIESCENCE IN LATENTLY INFECTED CELLS, FOLLOWED BY IMMUNE-MEDIATED CLEARANCE OF REACTIVATED CELLS. TO DATE, HUNDREDS OF COMPOUNDS HAVE BEEN INVESTIGATED FOR VIRAL REACTIVATION, YET NONE HAS RESULTED IN A FUNCTIONAL CURE. THE INSUFFICIENCY OF THESE LATENCY-REVERSING AGENTS (LRAS) ALONE INDICATES A CRITICAL NEED FOR ADDITIONAL, ALTERNATE APPROACHES SUCH AS GENETIC MANIPULATION. LONG NON-CODING RNAS (LNCRNAS) ARE AN EMERGING CLASS OF REGULATORY RNAS WITH FUNCTIONAL ROLES IN MANY CELLULAR PROCESSES, INCLUDING EPIGENETIC MODULATION. A NUMBER OF LNCRNAS HAVE ALREADY BEEN IMPLICATED TO PLAY IMPORTANT ROLES IN HIV-1 LATENCY AND, AS SUCH, PHARMACOLOGICAL MODULATION OF LNCRNAS CONSTITUTES A RATIONAL ALTERNATIVE APPROACH IN HIV-1 CURE RESEARCH. IN THIS REVIEW, WE DISCUSS THE CURRENT STATE OF KNOWLEDGE OF THE ROLE OF LNCRNAS IN HIV-1 INFECTION AND EXPLORE THE SCOPE FOR A LNCRNA-MEDIATED GENETIC APPROACH WITHIN THE SHOCK AND KILL STRATEGY OF HIV-1 CURE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  4636  27 NEUROLOGIC COMPLICATIONS OF ACUTE HIV INFECTION. PURPOSE OF REVIEW: THIS REVIEW FOCUSES ON THE PATHOPHYSIOLOGY OF ACUTE HIV INFECTION (AHI) AND RELATED CENTRAL NERVOUS SYSTEM (CNS) PATHOLOGY, THE CLINICAL CHARACTERISTICS OF NEUROLOGIC COMPLICATIONS OF AHI, AND THE IMPLICATIONS OF THE CNS RESERVOIR AND VIRAL ESCAPE FOR HIV TREATMENT AND CURE STRATEGIES. RECENT FINDINGS: RECENT STUDIES IN NEWLY SEROCONVERTED POPULATIONS SHOW A HIGH PREVALENCE OF PERIPHERAL NEUROPATHY AND COGNITIVE DYSFUNCTION IN AHI, EVEN THOUGH THESE FINDINGS HAVE BEEN CLASSICALLY ASSOCIATED WITH CHRONIC HIV INFECTION. HIV CURE STRATEGIES SUCH AS THE "SHOCK AND KILL" STRATEGY ARE CURRENTLY BEING STUDIED IN VITRO AND EVEN IN SMALL CLINICAL TRIALS, THOUGH THE CNS AS A RESERVOIR FOR LATENT HIV POSES UNIQUE BARRIERS TO THESE TREATMENT STRATEGIES. SUMMARY: LIMITED POINT OF CARE DIAGNOSTIC TESTING FOR AHI AND DELAYED RECOGNITION OF INFECTION CONTINUE TO LEAD TO UNDER-RECOGNITION AND UNDER-REPORTING OF NEUROLOGIC MANIFESTATIONS OF AHI. AHI SHOULD BE ON THE DIFFERENTIAL FOR A BROAD RANGE OF NEUROLOGICAL CONDITIONS, FROM BELL'S PALSY, PERIPHERAL NEUROPATHY, AND ASEPTIC MENINGITIS, TO MORE RARE MANIFESTATIONS SUCH AS ADEM, AIDP, MENINGO-RADICULITIS, TRANSVERSE MYELITIS, AND BRACHIAL NEURITIS. TREATMENT FOR THESE CONDITIONS INVOLVES EARLY INITIATION OF ANTIRETROVIRAL THERAPY (ART) AND THEN STANDARD PRESENTATION-SPECIFIC TREATMENTS. CURRENT HIV CURE STRATEGIES UNDER INVESTIGATION INCLUDE BONE MARROW TRANSPLANT, VIRAL RESERVOIR RE-ACTIVATION AND ERADICATION, AND GENOME AND EPIGENETIC VIRAL TARGETING. HOWEVER, CNS PENETRATION BY HIV-1 OCCURS EARLY ON IN THE DISEASE COURSE WITH THE ESTABLISHMENT OF THE CNS VIRAL RESERVOIR AND IS AN IMPORTANT LIMITING FACTOR FOR THESE THERAPIES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  2073  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18  4241  27 METHYLATION REGULATION OF ANTIVIRAL HOST FACTORS, INTERFERON STIMULATED GENES (ISGS) AND T-CELL RESPONSES ASSOCIATED WITH NATURAL HIV CONTROL. GWAS, IMMUNE ANALYSES AND BIOMARKER SCREENINGS HAVE IDENTIFIED HOST FACTORS ASSOCIATED WITH IN VIVO HIV-1 CONTROL. HOWEVER, THERE IS A GAP IN THE KNOWLEDGE ABOUT THE MECHANISMS THAT REGULATE THE EXPRESSION OF SUCH HOST FACTORS. HERE, WE AIMED TO ASSESS DNA METHYLATION IMPACT ON HOST GENOME IN NATURAL HIV-1 CONTROL. TO THIS END, WHOLE DNA METHYLOME IN 70 UNTREATED HIV-1 INFECTED INDIVIDUALS WITH EITHER HIGH (>50,000 HIV-1-RNA COPIES/ML, N = 29) OR LOW (<10,000 HIV-1-RNA COPIES/ML, N = 41) PLASMA VIRAL LOAD (PVL) LEVELS WERE COMPARED AND IDENTIFIED 2,649 DIFFERENTIALLY METHYLATED POSITIONS (DMPS). OF THESE, A CLASSIFICATION RANDOM FOREST MODEL SELECTED 55 DMPS THAT CORRELATED WITH VIROLOGIC (PVL AND PROVIRAL LEVELS) AND HIV-1 SPECIFIC ADAPTIVE IMMUNITY PARAMETERS (IFNG-T CELL RESPONSES AND NEUTRALIZING ANTIBODIES CAPACITY). THEN, CLUSTER AND FUNCTIONAL ANALYSES IDENTIFIED TWO DMP CLUSTERS: CLUSTER 1 CONTAINED HYPO-METHYLATED GENES INVOLVED IN ANTIVIRAL AND INTERFERON RESPONSE (E.G. PARP9, MX1, AND USP18) IN INDIVIDUALS WITH HIGH VIRAL LOADS WHILE IN CLUSTER 2, GENES RELATED TO T FOLLICULAR HELPER CELL (TFH) COMMITMENT (E.G. CXCR5 AND TCF7) WERE HYPER-METHYLATED IN THE SAME GROUP OF INDIVIDUALS WITH UNCONTROLLED INFECTION. FOR SELECTED GENES, MRNA LEVELS NEGATIVELY CORRELATED WITH DNA METHYLATION, CONFIRMING AN EPIGENETIC REGULATION OF GENE EXPRESSION. FURTHER, THESE GENE EXPRESSION SIGNATURES WERE ALSO CONFIRMED IN EARLY AND CHRONIC STAGES OF INFECTION, INCLUDING UNTREATED, CART TREATED AND ELITE CONTROLLERS HIV-1 INFECTED INDIVIDUALS (N = 37). THESE DATA PROVIDE THE FIRST EVIDENCE THAT HOST GENES CRITICALLY INVOLVED IN IMMUNE CONTROL OF THE VIRUS ARE UNDER METHYLATION REGULATION IN HIV-1 INFECTION. THESE INSIGHTS MAY OFFER NEW OPPORTUNITIES TO IDENTIFY NOVEL MECHANISMS OF IN VIVO VIRUS CONTROL AND MAY PROVE CRUCIAL FOR THE DEVELOPMENT OF FUTURE THERAPEUTIC INTERVENTIONS AIMED AT HIV-1 CURE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19  4255  21 METHYLOME-WIDE ANALYSIS OF CHRONIC HIV INFECTION REVEALS FIVE-YEAR INCREASE IN BIOLOGICAL AGE AND EPIGENETIC TARGETING OF HLA. HIV-INFECTED INDIVIDUALS ARE LIVING LONGER ON ANTIRETROVIRAL THERAPY, BUT MANY PATIENTS DISPLAY SIGNS THAT IN SOME WAYS RESEMBLE PREMATURE AGING. TO INVESTIGATE AND QUANTIFY THE IMPACT OF CHRONIC HIV INFECTION ON AGING, WE REPORT A GLOBAL ANALYSIS OF THE WHOLE-BLOOD DNA METHYLOMES OF 137 HIV+ INDIVIDUALS UNDER SUSTAINED THERAPY ALONG WITH 44 MATCHED HIV- INDIVIDUALS. FIRST, WE DEVELOP AND VALIDATE EPIGENETIC MODELS OF AGING THAT ARE INDEPENDENT OF BLOOD CELL COMPOSITION. USING THESE MODELS, WE FIND THAT BOTH CHRONIC AND RECENT HIV INFECTION LEAD TO AN AVERAGE AGING ADVANCEMENT OF 4.9 YEARS, INCREASING EXPECTED MORTALITY RISK BY 19%. IN ADDITION, SUSTAINED INFECTION RESULTS IN GLOBAL DEREGULATION OF THE METHYLOME ACROSS >80,000 CPGS AND SPECIFIC HYPOMETHYLATION OF THE REGION ENCODING THE HUMAN LEUKOCYTE ANTIGEN LOCUS (HLA). WE FIND THAT DECREASED HLA METHYLATION IS PREDICTIVE OF LOWER CD4 / CD8 T CELL RATIO, LINKING MOLECULAR AGING, EPIGENETIC REGULATION, AND DISEASE PROGRESSION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  6314  22 THE RELATIONSHIP BETWEEN THE EPIGENETIC AGING BIOMARKER "GRIMAGE" AND LUNG FUNCTION IN BOTH THE AIRWAY AND BLOOD OF PEOPLE LIVING WITH HIV: AN OBSERVATIONAL COHORT STUDY. BACKGROUND: AGE-RELATED COMORBIDITIES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE COMMON IN PEOPLE LIVING WITH HUMAN IMMUNODEFICIENCY VIRUS (PLWH). WE INVESTIGATED THE RELATIONSHIP BETWEEN COPD AND THE EPIGENETIC AGE OF THE AIRWAY EPITHELIUM AND PERIPHERAL BLOOD OF PLWH. METHODS: AIRWAY EPITHELIAL BRUSHINGS FROM 34 PLWH ENROLLED IN THE ST. PAUL'S HOSPITAL HIV BRONCHOSCOPY COHORT AND PERIPHERAL BLOOD FROM 378 PLWH ENROLLED IN THE STRATEGIC TIMING OF ANTIRETROVIRAL TREATMENT (START) STUDY WERE PROFILED FOR DNA METHYLATION. THE DNA METHYLATION BIOMARKER OF AGE AND HEALTHSPAN, GRIMAGE, WAS CALCULATED IN BOTH TISSUE COMPARTMENTS. WE TESTED THE ASSOCIATION OF GRIMAGE WITH COPD IN THE AIRWAY EPITHELIUM AND AIRFLOW OBSTRUCTION AS DEFINED BY AN FEV(1)/FVC<0.70, AND FEV(1) DECLINE OVER 6 YEARS IN BLOOD. FINDINGS: THE AIRWAY EPITHELIUM OF PLWH WITH COPD WAS ASSOCIATED WITH GREATER GRIMAGE RESIDUALS COMPARED TO PLWH WITHOUT COPD (BETA=3.18, 95%CI=1.06-5.31, P=0.005). IN BLOOD, FEV(1)/FVC<LLN WAS ASSOCIATED WITH GREATER GRIMAGE RESIDUALS (BETA=1.74, 95%CI=0.37-3.24, P=0.019). FEV(1) DECLINE WAS INVERSELY CORRELATED WITH GRIMAGE RESIDUALS IN BLOOD (R=-0.13, P=0.012). PLWH WHO HAD NORMAL LUNG FUNCTION BUT WHO SUBSEQUENTLY DEVELOPED AN FEV(1)/FVC<0.70 OVER THE COURSE OF 6 YEARS HAD HIGHER GRIMAGE RESIDUALS AT BASELINE (BETA=2.33, 95%CI=0.23-4.44, P=0.031). INTERPRETATION: GRIMAGE MAY REFLECT LUNG AND SYSTEMIC EPIGENETIC CHANGES THAT OCCUR WITH ADVANCED AIRFLOW OBSTRUCTION AND MAY HELP TO IDENTIFY PLWH WITH A HIGHER RISK OF DEVELOPING COPD. FUNDING: CANADIAN INSTITUTES OF HEALTH RESEARCH AND THE BRITISH COLUMBIA LUNG ASSOCIATION. THE START SUBSTUDY WAS FUNDED BY NIH GRANTS: UM1-AI068641, UM1-AI120197, AND RO1HL096453.	2022