R01MH128155

Novel Macrophage-Tropic Transmitted/Founder SHIV Model of CNS Persistence to Evaluate CRISPR/Cas9 Gene Editing - Project Summary/Abstract.

An eradication HIV cure requires safe and effective clearance of replication competent virus from all reservoirs, including the brain. Characterization of the CNS reservoir and empiric testing of novel cure strategies require physiologically relevant animal models of HIV persistence in the brain.

Here, we propose to integrate major advances from our groups in SHIV NHP models and AAV-delivered CRISPR/Cas9 editing to delineate key features of the CNS reservoir and determine the efficacy of CRISPR-based eradication in the brain.

Transmitted/Founder (TF) SHIVs, which encode minimally adapted TF HIV-1 Envs, represent a major advance in biologically relevant NHP models. TF SHIVs have demonstrated robust replication in rhesus macaques, with viral kinetics, cell tropism, and pathogenesis that mirror HIV-1 infection of humans. Further, they have recently been shown to faithfully recapitulate virus-host interactions, persist through suppressive ART, and rebound with similar kinetics and clonality as HIV-1.

Here, we will employ a novel, genetically barcoded TF SHIV model of CNS pathogenesis and persistence, based on TF SHIV.D.191859 (SHIV.D), which encodes a clade D TF HIV-1 Env that is CCR5-tropic, efficiently replicates in CD4 T cells and monocyte-derived macrophages, and demonstrates consistent CNS replication, pathogenesis, and persistence.

Using this barcoded TF SHIV.D model of CNS persistence, we will test a novel all-in-one AAV9-mediated CRISPR/Cas9 gene editing system. A recent first-in nonhuman-primate study of SIV-infected rhesus macaques demonstrated the tolerability and efficacy of this approach. The AAV9-CRISPR-Cas9 was broadly distributed across tissues, leading to cleavage and excision of the SIV genome and substantial reductions in the size of the proviral reservoir across tissues. Notably, the AAV was well distributed within the CNS resulting in excision of provirus across brain regions.

In this application, we will leverage advances in the macrophage-tropic barcoded SHIV.D model and AAV-delivered CRISPR/Cas9 editing to gain insight on CNS neuropathogenesis and persistence. Our hypothesis is that by (i) characterizing SHIV.D persistence in key CNS cells and tissues, (ii) optimizing AAV-delivered CRISPR-Cas9 approaches for SHIV.D persistence in the brain, and (iii) testing the effects of global and myeloid-targeting CRISPR approaches on CNS reservoir reduction in vivo, we will advance prospects for eradicating HIV from the brain.

If this hypothesis is affirmed, the significance to the HIV cure field would be substantial, since it would improve our understanding of the CNS reservoir, develop a robust model for HIV pathogenesis and persistence in the brain, and provide key pre-clinical data on the safety and efficacy of a promising CRISPR-based cure strategy.

Trustees Of The University Of Pennsylvania

THE MISSION OF THE NATIONAL INSTITUTE OF MENTAL HEALTH (NIMH) IS TO TRANSFORM THE UNDERSTANDING AND TREATMENT OF MENTAL ILLNESSES THROUGH BASIC AND CLINICAL RESEARCH, PAVING THE WAY FOR PREVENTION, RECOVERY, AND CURE. IN MAY 2020, NIMH RELEASED ITS NEW STRATEGIC PLAN FOR RESEARCH. THE NEW STRATEGIC PLAN BUILDS ON THE SUCCESSES OF PREVIOUS NIMH STRATEGIC PLANS BY PROVIDING A FRAMEWORK FOR SCIENTIFIC RESEARCH AND EXPLORATION, AND ADDRESSING NEW CHALLENGES IN MENTAL HEALTH. THE NEW STRATEGIC PLAN OUTLINES FOUR HIGH-LEVEL GOALS: GOAL 1: DEFINE THE BRAIN MECHANISMS UNDERLYING COMPLEX BEHAVIORS GOAL 2: EXAMINE MENTAL ILLNESS TRAJECTORIES ACROSS THE LIFESPAN GOAL 3: STRIVE FOR PREVENTION AND CURES GOAL 4: STRENGTHEN THE PUBLIC HEALTH IMPACT OF NIMH-SUPPORTED RESEARCH THESE FOUR GOALS FORM A BROAD ROADMAP FOR THE INSTITUTE'S RESEARCH PRIORITIES OVER THE NEXT FIVE YEARS, BEGINNING WITH THE FUNDAMENTAL SCIENCE OF THE BRAIN AND BEHAVIOR, AND EXTENDING THROUGH EVIDENCE-BASED SERVICES THAT IMPROVE PUBLIC HEALTH OUTCOMES. THE INSTITUTE'S OVERALL FUNDING STRATEGY IS TO SUPPORT A BROAD SPECTRUM OF INVESTIGATOR-INITIATED RESEARCH IN FUNDAMENTAL SCIENCE, WITH INCREASING USE OF INSTITUTE-SOLICITED INITIATIVES FOR APPLIED RESEARCH WHERE PUBLIC HEALTH IMPACT IS A SHORT-TERM MEASURE OF SUCCESS. THE NEW STRATEGIC PLAN ALSO ADDRESSES A NUMBER OF CROSS-CUTTING THEMES THAT ARE RELEVANT TO ALL RESEARCH SUPPORTED BY NIMH, THESE THEMES HIGHLIGHT AREAS WHERE NIMH-FUNDED SCIENCE MAY HAVE THE GREATEST IMPACT, BRIDGE GAPS, AND OFFER NOVEL APPROACHES TO ACCELERATE ADVANCES IN MENTAL HEALTH RESEARCH. FOR EXAMPLE, NIMH VALUES A COMPREHENSIVE RESEARCH AGENDA THAT TAKES AN INCLUSIVE APPROACH THAT ENSURES RESEARCH INTERESTS ARE VARIED, MAINTAIN DIVERSE PARTICIPATION AND PARTNERSHIPS, AND ACHIEVE RESEARCH GOALS ACROSS MULTIPLE TIMEFRAMES. THIS INCLUDES DIVERSE METHODOLOGIES, TOOLS, AND MODELS, RESEARCH ADDRESSING COMPLEX BASIC, TRANSLATIONAL, AND APPLIED QUESTIONS, RESEARCH INCLUDING BOTH SEXES AND, AS APPROPRIATE, GENETIC BACKGROUND, AND, PARTICIPANTS FROM DIVERSE RACIAL AND ETHNIC BACKGROUNDS, AND ACROSS GENDER IDENTITIES, GEOGRAPHICAL CONTEXT, SOCIOECONOMIC STATUS, NEUROTYPE, AND AGE OFFERING THE BEST POSSIBLE REPRESENTATION, FOR THE BROADEST NUMBER OF INDIVIDUALS WHO MAY ULTIMATELY BENEFIT FROM THESE SCIENTIFIC ADVANCES. TO ACCOMPLISH THE GOALS OUTLINED IN THE NEW STRATEGIC PLAN, NIMH WILL SUPPORT RESEARCH THAT AIMS: TO CHARACTERIZE THE GENOMIC, MOLECULAR, CELLULAR, AND CIRCUIT COMPONENTS CONTRIBUTING TO BRAIN ORGANIZATION AND FUNCTION, TO IDENTIFY THE DEVELOPMENTAL, FUNCTIONAL, AND REGULATORY MECHANISMS RELEVANT TO COGNITIVE, AFFECTIVE, AND SOCIAL DOMAINS, ACROSS UNITS OF ANALYSIS, AND, TO GENERATE AND VALIDATE NOVEL TOOLS, TECHNIQUES, AND MEASURES TO QUANTIFY CHANGES IN THE ACTIVITY OF MOLECULES, CELLS, CIRCUITS, AND CONNECTOMES. TO DISCOVER GENE VARIANTS AND OTHER GENOMIC ELEMENTS THAT CONTRIBUTE TO THE DEVELOPMENT OF MENTAL ILLNESSES IN DIVERSE POPULATIONS, TO ADVANCE OUR UNDERSTANDING OF THE COMPLEX ETIOLOGY OF MENTAL ILLNESSES USING MOLECULAR EPIDEMIOLOGIC APPROACHES THAT INCORPORATE INDIVIDUAL GENETIC INFORMATION IN LARGE COHORTS, TO ELUCIDATE HOW HUMAN GENETIC VARIATION AFFECTS THE COORDINATION OF MOLECULAR, CELLULAR, AND PHYSIOLOGICAL NETWORKS SUPPORTING HIGHER-ORDER FUNCTIONS AND EMERGENT PROPERTIES OF NEUROBIOLOGICAL SYSTEMS, AND, TO DEVELOP NOVEL TOOLS AND TECHNIQUES FOR THE ANALYSIS OF LARGE-SCALE GENETIC, MULTI-OMIC DATA AS IT APPLIES TO MENTAL HEALTH. TO UTILIZE CONNECTOMIC APPROACHES TO IDENTIFY BRAIN NETWORKS AND CIRCUIT COMPONENTS THAT CONTRIBUTE TO VARIOUS ASPECTS OF MENTAL FUNCTION AND DYSFUNCTION, TO DETERMINE THROUGH BRAIN-WIDE ANALYSIS HOW CHANGES IN THE PHYSIOLOGICAL PROPERTIES OF MOLECULES, CELLS, AND CIRCUITS CONTRIBUTE TO MENTAL ILLNESSES, TO DEVELOP MOLECULAR, CELLULAR, AND CIRCUIT-LEVEL BIOMARKERS OF IMPAIRED NEURAL FUNCTION IN HUMANS, AND, TO DEVELOP INNOVATIVE TECHNOLOGIES, INCLUDING NEW IMAGING, COMPUTATIONAL, PHARMACOLOGICAL, AND GENETIC TOOLS TO INTERROGATE AND MODULATE CIRCUIT ACTIVITY AND STRUCTURE ALTERED IN MENTAL ILLNESSES. TO ELUCIDATE THE MECHANISMS CONTRIBUTING TO THE TRAJECTORIES OF BRAIN DEVELOPMENT AND BEHAVIOR, AND, TO CHARACTERIZE THE EMERGENCE AND PROGRESSION OF MENTAL ILLNESSES, AND IDENTIFYING SENSITIVE PERIODS FOR OPTIMAL INTERVENTION. TO DETERMINE EARLY RISK AND PROTECTIVE FACTORS, AND RELATED MECHANISMS, TO SERVE AS NOVEL INTERVENTION GROUPS, AND, TO DEVELOP RELIABLE AND ROBUST BIOMARKERS AND ASSESSMENT TOOLS TO PREDICT ILLNESS ONSET, COURSE, AND ACROSS DIVERSE POPULATIONS. TO DEVELOP NOVEL INTERVENTIONS USING A MECHANISM-INFORMED, EXPERIMENTAL THERAPEUTICS APPROACH, AND, TO DEVELOP AND IMPLEMENT MEASUREMENT STRATEGIES TO FACILITATE MECHANISM-BASED INTERVENTION DEVELOPMENT AND TESTING. TO INVESTIGATE PERSONALIZED INTERVENTION STRATEGIES ACROSS DISEASE PROGRESSION AND DEVELOPMENT, AND, TO DEVELOP AND REFINE COMPUTATIONAL APPROACHES AND RESEARCH DESIGNS THAT CAN BE USED TO INFORM AND TEST PERSONALIZED INTERVENTIONS. TO DEVELOP AND TEST APPROACHES FOR ADAPTING, COMBINING, AND SEQUENCING INTERVENTIONS TO ACHIEVE THE GREATEST IMPACT ON THE LIVES AND FUNCTIONING OF PERSONS SEEKING CARE, TO CONDUCT EFFICIENT PRAGMATIC TRIALS THAT EMPLOY NEW TOOLS TO RAPIDLY IDENTIFY, ENGAGE, ASSESS, AND FOLLOW PARTICIPANTS IN THE CONTEXT OF ROUTINE CARE, AND, TO ENHANCE THE PRACTICAL RELEVANCE OF EFFECTIVENESS RESEARCH VIA DEPLOYMENT-FOCUSED, HYBRID, EFFECTIVENESS-IMPLEMENTATION STUDIES. TO EMPLOY ASSESSMENT PLATFORMS WITHIN HEALTHCARE SYSTEMS TO ACCURATELY ASSESS THE DISTRIBUTION AND DETERMINANTS OF MENTAL ILLNESSES AND TO INFORM STRATEGIES FOR IMPROVED SERVICES, TO OPTIMIZE REAL-WORLD DATA COLLECTION SYSTEMS TO IDENTIFY STRATEGIES FOR IMPROVING ACCESS, QUALITY, EFFECTIVENESS, AND CONTINUITY OF MENTAL HEALTH SERVICES, AND, TO COMPARE ALTERNATIVE FINANCING MODELS TO PROMOTE EFFECTIVE AND EFFICIENT CARE FOR INDIVIDUALS WITH SERIOUS EMOTIONAL DISTURBANCES AND SERIOUS MENTAL ILLNESSES. TO STRENGTHEN PARTNERSHIPS WITH KEY STAKEHOLDERS TO DEVELOP AND VALIDATE STRATEGIES FOR IMPLEMENTING, SUSTAINING, AND CONTINUOUSLY IMPROVE EVIDENCE-BASED PRACTICES, TO BUILD MODELS TO SCALE-UP EVIDENCE-BASED PRACTICES FOR USE IN PUBLIC AND PRIVATE PRIMARY CARE, SPECIALTY CARE AND OTHER SETTINGS, AND, TO DEVELOP DECISION-SUPPORT TOOLS AND TECHNOLOGIES THAT INCREASE THE EFFECTIVENESS AND CONTINUOUS IMPROVEMENT OF MENTAL HEALTH INTERVENTIONS IN PUBLIC AND PRIVATE PRIMARY CARE, SPECIALTY CARE, AND OTHER SETTINGS. TO ADAPT, VALIDATE, AND SCALE-UP PROGRAMS CURRENTLY IN USE THAT IMPROVE MENTAL HEALTH SERVICES FOR UNDERSERVED POPULATIONS, TO DEVELOP AND VALIDATE SERVICE DELIVERY MODELS THAT PROVIDE EVIDENCE-BASED CARE FOR INDIVIDUALS THROUGHOUT THE COURSE OF MENTAL ILLNESS, TO DEVELOP AND VALIDATE SYSTEMS-LEVEL STRATEGIES USING TECHNOLOGY AND OTHER APPROACHES, TO IDENTIFY, SUPPORT, AND MONITOR THE EFFECTIVENESS OF EVIDENCE-BASED CARE THROUGHOUT THE COURSE OF ILLNESS, AND, TO DEVELOP AND VALIDATE DECISION-MAKING MODELS THAT BRIDGE MENTAL HEALTH, MEDICAL, AND OTHER CARE SETTINGS TO INTEGRATE THE APPROPRIATE CARE FOR PEOPLE WITH SERIOUS MENTAL ILLNESSES AND COMORBID MEDICAL CONDITIONS.

93.242 - Mental Health Research Grants

National Institute of Mental Health (NIMH) [HHS - NIH]

Philadelphia, Pennsylvania 191044875 United States

Single Zip Code

Role of Myeloid Cells in Persistence and Eradication of HIV-1 Reservoirs from the Brain (R01 Clinical Trial Not Allowed) (RFA-MH-20-701)

Amendment Since initial award the total obligations have increased 312% from $1,133,540 to $4,668,329.