Robert Gross, MD - US grants

PROJECT SUMMARY Epilepsy, occurring in 1 percent of the world?s population, is associated with disability, injury, cognitive and neurological dysfunction, depression, loss of productivity, socioeconomic decline and even death. Of this population, 30 percent of epilepsy cases are medically intractable, leaving surgical interventions as the only option for treatment. Whereas open resection, the current surgical standard of treatment, can yield seizure freedom rates as high as 60-80 percent, these are often associated with cognitive dysfunction and focal neurological deficits. Particularly, patients with dominant hemisphere mesial temporal lobe epilepsy (MTLE), the target population for this proposal, are at risk for significant decline in memory and associated disability. The only option for these patients at present is electrical neuromodulation which, although effective at reducing seizures, only achieves seizure freedom in ~10% of patients. We have recently found that delivering asynchronous pulses distributed across a multielectrode array of 16 microelectrodes, and stimulated at low (theta) frequency, is more effective than macrostimulation in controlling seizures in a rodent model of MTLE. The objective of the proposed project is to optimize asynchronous distributed multielectrode stimulation (ADMES) in a realistic large animal model of epilepsy - non-human primates (NHP) that have been administered penicillin (PCN) in the hippocampus to induced repeated spontaneous seizures. This research will capitalize on the availability of a new commercial neurostimulation system (RC+S, Medtronic) that uniquely allows our novel approach to be implemented. We will also exploit the novel bi-directional feature of this unit to optimize our therapy with both open-loop and closed-loop approaches to ADMES. We will first implement ADMES in our NHP model and quantify effects on seizure frequency and length, and rule out adverse effects on recognition memory. In parallel, we will characterize the response of physiological biomarkers such as synchrony to adjustment of ADMES stimulation in an externalized system. This will allow us to develop both open-loop and closed-loop control policies to optimize these biomarkers as a proxy for seizure control. The most effective stimulation parameters will be implemented in 8 NHPs using the RC+S neurostimulator and benefit on seizure frequency and effects on memory will be evaluated. If seizure reduction is ?50% then we will advance to an early clinical feasibility study. For this, we will first identify electrophysiological biomarkers and characterize the effects of stimulation parameters informed from our NHP study on those biomarkers during invasive monitoring of MTLE patients and then move to an early feasibility trial of ADMES in 6 patients. The final stimulation parameters will be implemented in RC+S and behavioral seizure reduction and memory testing for safety will be quantified over 12 months. At the completion of this aim we will have demonstrated the feasibility of using ADMES and the RC+S; positive results should lay the foundation for a larger clinical trial for MTLE, with possible application to the other epilepsies. This research capitalizes on a strong academic/industry/national laboratory collaboration between clinicians, scientists and engineers, and a rational, stepwise translational approach through a realistic animal model to early feasibility testing in patients, to bring new neurotechnology and control theory applications to bear on a major health concern.

DESCRIPTION (provided by applicant): Stroke remains a leading cause of human death and disability while very few effective treatments are available for stroke patients. Stem cell transplantation therapy provides the possibility to regenerate and repair damaged brain tissues after ischemic stroke. The investigation takes a comprehensive and unprecedented approach to promote both trophic supports as well as cell replacement potential of pluripotent stem cells to develop a highly effective stem cell therapy for ischemic stroke. We propose that enhancing the survival and regenerative properties of transplanted cells as well as an improved host environment are critical for a successful stem cell stroke therapy. To reach this goal, our previous and preliminary studies have demonstrated a marked protective effect and increased functional benefits of combining hypoxia preconditioning (HP) and other regenerative strategies including optogenetic techniques and up regulated multiple trophic factors in the ischemic brain promoted by peripheral stimulation. Our central hypothesis is that a combination strategy of HP-primed NPCs subjected to optogenetic manipulations and improved host environment will allow better survival of transplanted as well as endogenous cells, enhance neurogenesis/angiogenesis via both exogenous and endogenous mechanisms, and results in optimal tissue repair and functional recovery after stroke. In neural progenitor cells (NPCs) derived from mouse induced pluripotent stem (iPS) cells, we will express the blue light- sensitive channelrhodopsin (ChR) channels and test the possibility that activation of ChRs by blue light stimuli or by the luciferase/ChR proten (luminopsis) substrate coelenterazine (CTZ) is a feasible and effective method to improve and evaluate neuronal differentiation, integration into host neural networks and neuronal connections after transplantation into the ischemic brain. We will examine the strategies to promote tissue repair and provide evidence for the morphological and functional restoration of ischemic brain structures in the unique barrel cortex ischemic stroke model of mice. We will demonstrate the feasibility and benefits of expression/activation of ChR channels in iPS-NPCs in vitro (Specific Aim 1) and after implantation into the post-ischemic barrel cortex (Aim 2). Based on the well-defined whisker- thalamus-barrel cortex pathway, structural and functional restoration of disrupted whisker-barrel activities will be evaluated usin a combination of cell specific and neuronal pathway specific measurements, including optogenetic, electrophysiological and optical imaging recordings (Aim 3). The proposal is from three research laboratories with complementary expertise in biophysics, electrophysiology, cellular/molecular biology and clinical neurosciences. The demonstration of cellular and tissue repairing benefits of iPS-NPCs in a particular brain structure is critical for the development of mechanism based cell transplantation therapy and the strategies will have great impacts on pre-clinical and clinical studies.

DESCRIPTION (provided by applicant): The University of Pennsylvania (Penn), in collaboration with the University of Botswana and the Ministry of Health, submits this application to train a small cadre of Batswana health professionals in HIV clinical research. Studies will address issues in treatment of HIV disease and co-infections in HIV- infected adults and children, treatment of malignancies and aging-related non-communicable diseases HIV infected adults, complications of HIV-exposure in uninfected children, and risk reduction in highly exposed uninfected women. This program will act as a catalytic agent to establish an extended research group in Botswana to address some of its pressing health problems identified by the Botswana Ministry of Health and which are consonant with the agendas of both Fogarty and PEPFAR. This proposal includes a close working relationship with the large Center for Clinical Epidemiology and Biostatistics at Penn, which will enable the new research unit in Botswana to function at a highly professional level from its establishment. Training. The training will have tw pathways. (1) Independent Investigator training. Batswana trainees will enroll in Penn's Master of Science in Clinical Epidemiology (MSCE) of which the first year will be spent on coursework at Penn and the second year on a research project in Botswana. The program aims to take 8 trainees over the 5-year program. Trainees will be paired with epidemiology and biostatistics mentors, and Botswana-based clinical and research experts to create an ideal environment for both their intellectual development and practical hand-on application of principles in the pursuit of new knowledge. These trainees will ultimately form the core of an extended research group, which will take the quality and quantity of clinical HIV research emanating from the University of Botswana and the Ministry of Health to a new level. (2) Associate Investigator training. This pathway will provide a series of 1- to 5-day modules to be conducted in Botswana, for health administrators, health clinicians, and research coordinators. The goal is to build in- country capacity to conduct locally driven investigation by empowering Associate Investigators to join collaborative teams led by the Independent Investigator trainees in their current and future research projects. These teams will be strengthened by an innovative teach-back approach in which the projects are used as training examples for the Independent Investigators to implement teaching skills and the Associate Investigator trainees to be become more intellectually vested in the projects. Institutional participation. The proposed training program will involve three key institutions in Botswana: the Faculty of Health Sciences at the University of Botswana, the Ministry of Health of Botswana, and the Botswana-UPenn Partnership. Investigators will leverage ongoing federally funded projects at the Botswana- UPenn Partnership to accelerate the pace of the development of their own research programs. Independent Investigators will take positions at either the University of Botswana or the Ministry of Health, where they will be guaranteed supported time to conduct research projects, and will form the nucleus of an extended group dedicated to research on HIV and associated diseases clinical research.

PROJECT SUMMARY/ABSTRACT The Emory MSTP prepares highly gifted and motivated students to pursue careers as physician-scientists and leaders in biomedical research. This approximately eight year training program leads to both M.D. and Ph.D. degrees in a clearly defined curricular path. The MD/PhD Program director and co-directors, under the advisement of an Executive Committee comprised of institutional leadership representing the academic units involved in training, is responsible for the leadership and oversight of the program. Selection of applicants is highly competitive and is made by a distinct MD/PhD Admissions Committee after extensive evaluation of prior scholarship and research experience, review of letters of recommendation, and in-depth interviews to assess the potential for success as physicians-scientists. The program allows for great flexibility in graduate program affiliation, as well as the sequence and duration of clinical or research training, but most trainees follow a typical curricular sequence: Preclinical medical science - PhD research and training - Clinical apprenticeship to complete the MD. Students can engage in laboratory research in the summer prior to the first year of Medical School. Trainees pursue dissertation research in a variety of outstanding graduate programs, including any of eight interdisciplinary biomedical training programs in the Laney Graduate School Division of Biological and Biomedical Sciences, in the Biomedical Engineering Program offered by a unique combined Department of Biomedical Engineering of Georgia Tech and Emory, in any of the six doctoral programs in the Rollins School of Public Health, or in any of the departmental graduate programs of Emory College (examples, Chemistry, Anthropology, Sociology). Each trainee completes at least 17 months of clinical training after defending his/her thesis with a flexible reentry window. The tremendous expansion of the research and clinical infrastructure at Emory and increased institutional support has facilitated the successful growth and development of this MSTP.

?-Synucleinopathies are neurodegenerative diseases characterized by intracellular inclusions of ?-synuclein (?- syn) aggregates and they include conditions such as Parkinson?s Disease (PD) and Dementia with Lewy Bodies (DLB). A prevailing view is that disease-associated factors such as aging compromise the ability of neurons to efficiently clear abnormally folded proteins which leads to the formation of intracellular aggregates and neurodegeneration. While enhancing the clearance of misfolded ?-syn is a potential therapeutic strategy for PD, current methods to activate cellular mechanisms for protein degradation rely mostly on pharmacological inducers or conventional gene delivery interventions. A translational roadblock in these approaches is the lack of control over dosage, precise time of intervention, and undesirable effects associated with the broad and sustained modulation of cellular degradation pathways. To address these therapeutic needs, we propose to develop a responsive gene therapy for the self-sufficient delivery of a neuroprotective therapy targeting the clearance of misfolded ?-syn species. In a cellular model of ?-syn seeded aggregation, we will demonstrate that our gene therapy approach can detect biological responses associated with the accumulation of ?-syn (Aim 1) and respond by modulating protein degradation pathways accordingly (Aim 2). We expect the outcomes of this project to enable a strategy where a therapy is produced as needed by the affected brain regions, opening the possibility to intervene at an early stage for the treatment of otherwise intractable neurodegenerative conditions such as PD. This project has the potential to be transformative as it introduces a modular platform technology with translational potential for other neurological targets linked to the neurotoxic behavior of misfolded proteins (e.g. amyloid-?, tau).

Core I: International ABSTRACT The International Core (Core I) is focused on developing clinical and patient-oriented adult and pediatric HIV/AIDS research and research capacity in Botswana, a country in southern Africa with one of the world's highest rates of HIV infection, but with excellent infrastructure and strong commitment to advancing AIDS clinical programs for its population and promoting HIV-related research and research capacity. The Core's missions are to nucleate new collaborations among Penn and Botswana-based investigators and provide infrastructure for studies implemented in Botswana that will advance high priority research relevant to the country, and to train the next generation of US- and Botswana-based HIV/AIDS investigators. The Core's focus remains cutting edge by maintaining close relationships and conducting strategic planning with Botswana-based stakeholders including the University of Botswana (UB) & Ministry of Health and Wellness, and working closely with other CFAR cores for synergy. Core I is led by Drs. Robert Gross (Director, based at Penn) and Tonya Arscott-Mills (Co-Director, in Botswana), along with Core Investigators Drs. Andrew Steenhoff (at CHOP) and Billy Tsima (at UB); Dr. Tsima joined Core I this year after receiving his MSCE in a Core I training program and appointment to the UB faculty. Operations are facilitated by the facts that both Drs. Arscott-Mills & Tsima are based in Botswana, English is an official language, and Core I leverages resources of the institutionally-funded Botswana-UPenn Partnership. Core research services include (1) consulting on feasibility and local appeal of research ideas targeting issues and populations in Botswana; (2) engaging key stakeholders and local collaborators to ensure optimal design and efficient implementation of projects; (3) support for protocols including assistance with IRB submissions and translation of materials into the local language (Setswana) to allow for full local participation; (4) hiring, training and supervising local research staff; (5) specimen processing and laboratory analyses or shipping; and (6) secure data management. Core training activities include mentoring of junior investigators from Penn and Botswana who are developing HIV-related research in Botswana; partnering with new-to-HIV and/or new-to- Botswana established investigators; sponsoring seminar at UB and at Penn to disseminate findings & engage investigators; teaching epidemiology & biostatistics skills to aspiring researchers from the US and Botswana; and teaching laboratory skills including hands-on experimental work at Core in-country laboratories. In the current reporting period Core I enabled high priority research on HIV acquisition & treatment; opportunistic infection diagnosis, transmission, treatment and outcomes (particularly TB & cryptococcosis); the intersection of severe mental illness and HIV; HIV in children, adolescents and women; and cervical cancer. Looking ahead, planned innovations include establishing a local Community Advisory Board (CAB); implementing a new project database to more efficiently manage resources; and catalyzing research on key local priorities including advancing interventions for prevention in HIV-negative and reducing comorbidities in HIV-infected individuals.

The advent of anti-retroviral therapy (ART) for people living with HIV/AIDS (PLWHA) substantially improved life expectancy but, now, PLWHA who smoke lose more life-years due to tobacco use than they do to their HIV infection. Unfortunately, the rate of smoking among PLWHA in the US is about 40%. The limited tobacco use treatment research with PLWHA indicates that behavioral treatments and medications (nicotine patch and varenicline) yield moderate effects on cessation, with quit rates that are considerably lower than they are for the general population. Thus, there is a critical need to identify novel ways to optimize tobacco cessation treatment for smokers with HIV. Two factors are highly predictive of cessation outcomes with pharmacotherapy, in the general population and among PLWHA. First, a smoker's rate of nicotine metabolism, characterized by the nicotine metabolite ratio (NMR, a marker of CYP2A6 gene variants), predicts cessation both for varenicline and nicotine patch. Our studies with general population and HIV-infected smokers show that personalizing the choice of medications for smokers using the NMR can increase efficacy and reduce toxicities, an approach highlighted by the NCI (https://www.cancer.gov/about-nci/budget/plan/public-health). Second, adherence to smoking cessation medications, in the general population and among PLWHA, rarely exceeds 60% and non-adherence lowers cessation rates 2-3 fold. We developed the Managed Problem Solving (MAPS) intervention which is endorsed by the CDC (https://www.cdc.gov/hiv/research/interventionresearch/compendium/ma/index.html) as an evidence-based intervention for medication adherence among PLWHA. Thus, the application's premise is that incorporating intervention components to tailor tobacco use medications (varenicline or patch) with the NMR and increase adherence to the medication using MAPS will optimize tobacco treatments for PLWHA. To test this premise, we will conduct a rigorous multi-site randomized clinical trial with 488 HIV+ smokers to evaluate NMR-tailored treatment and MAPS as optimization strategies for tobacco dependence treatment for PLWHA. We will use a factorial design to examine: 1) The effects of the NMR-tailored and/or MAPS interventions on end- of-treatment (EOT) and 6-month smoking cessation rates (primary aim); 2) Mediators of the NMR-tailored and MAPS interventions (secondary aim); and 3) Moderators of the NMR-tailored and MAPS interventions (exploratory aim). Our overall approach is consistent with the Multiphase Optimization Strategy which has gained prominence for guiding the evaluation of interventions for enhancing tobacco use treatment effectiveness. Addressing these aims will determine: the use of adherence and pharmacogenetic optimization of smoking cessation treatment for PLWHA, the mechanisms that underlie the effects of these optimization strategies on cessation outcomes, and the variation in the effects of these optimization strategies across sub-groups of PLWHA. In the end, this trial will help understand if getting the right medication to the right person and helping to make sure they sufficiently use that medication optimizes tobacco cessation treatment for this population.

PROJECT SUMMARY Smoking rates in people living with HIV (PLWH) exceed 40%, nearly 3x uninfected individuals. Cardiovascular disease (CVD), including myocardial infarction (MI), is common in PLWH, in part due to smoking. Despite availability of smoking cessation pharmacotherapy, cessation rates among PLWH remain low. Frameworks for understanding smoking cessation emphasize biological, psychological, and social factors. However, critical gaps in identifying and addressing biological factors related to tobacco use among PLWH remain. In the general population, the rate at which nicotine is metabolized is an important biomarker of smoking behavior and treatment response. Greater CYP2A6 enzyme activity, as measured by higher nicotine metabolite ratios (NMR), results in: faster nicotine clearance, more cigarettes smoked per day, higher nicotine dependence, greater severity of withdrawal symptoms and reduced cessation. Recent work from our lab found significantly higher NMRs in HIV suggesting effects in HIV may differ. Differences in NMR may be affected by HIV infection and/or antiretroviral therapy (ART). HIV itself may increase NMR as CYP2A6 is induced by inflammation, which may mirror dysregulation caused by HIV infection. ART drugs may alter NMR via other mechanisms: they may reduce NMR by reducing inflammation via viral suppression, reduce NMR via CYP2A6 inhibition, or increase NMR via CYP2A6 induction. And these mechanisms may differ by ART drug. Moreover, the impact of higher NMR on smoking and complications of smoking (e.g., MI) among PLWH are currently unknown. Higher NMR influences smoking topography (e.g., higher puff volume), which is associated with greater exposure to inducers of inflammation and coagulation. While higher NMR increases lung cancer risk, its effect on MI is unknown. We propose to: 1) determine whether NMR is faster after HIV infection, relative to before, 2) determine whether viral suppression decreases NMR and whether the effect differs by ART drugs which do and do not alter CYP2A6 activity, 3) determine whether lower NMR predicts higher smoking cessation rates in PLWH on ART with viral suppression, and 4) determine whether NMR is a risk factor for MI in PLWH. We will conduct retrospective cohort studies with paired specimens for Aims 1 and 2 and nested case-control studies for Aims 3 and 4. Data and specimens will be obtained from the Multicenter AIDS Cohort Study (MACS) /Women's Intra-agency Health Study (WIHS) and the CFAR Network Integrated Clinical Systems (CNICS) databases and specimen repositories. Elucidating the relationship between HIV, ART, and smoking, may lead to the development of targeted interventions for smokers with HIV infection such as adding drugs that decrease CYP2A6 activity or switching off ART drugs that induce CYP2A6. If NMR is a predictor of MI, it will help us identify a subpopulation of PLWH in more urgent need of interventions. Smokers with HIV lose more life years to tobacco use than to HIV, partly due to increases in smoking-related comorbidities including CVD. Thus, interventions targeting HIV+ smokers may substantially reduce mortality globally.

PROJECT SUMMARY/ABSTRACT Epileptic seizures can be characterized as concerted and synchronized activity of neurons across the brain for an extended period of time. We hypothesize that, as for other normal brain-controlled behavior, epileptic seizures are not caused by random activity of neurons, but rather arise from activity in a specific, organized brain network. Our overarching goal is to elucidate such a seizure-specific network in the brain and to deliver genetic neuromodulation specifically to such a seizure-generating network for tailored seizure suppression. In our proposal, we first identify all the critical brain cells that make up that seizure network in acute and chronic rodent models of epilepsy. Then, we will manipulate such a network to stop seizure occurrence. We will identify and visualize brain structures and cells responsible for generation of seizures in the whole brain by labeling these cells with a fluorescent protein tag utilizing sophisticated gene expression techniques in genetically modified mice (Specific Aim 1). This seizure-specific labelling of neurons occurs when they exhibit extensive activity in the presence of a chemical in the system during a seizure episode. This labelling procedure will be repeated to examine if the same neuronal populations become active in two separate episodes of seizures. The cells labeled with the fluorescence reporter will be examined by fluorescence microscopy. Overlapped labelling of neurons between two seizure episodes will support our hypothesis that the same subset of neurons is repeatedly involved in generation of seizures. We will then employ a similar strategy to deliver genetic neuromodulation to a seizure-generating network (Specific Aim 2). We engineered a viral vector that carries a molecular tool that suppress neuronal activity when an activating drug is injected into the animal. This viral vector will be injected into a brain region responsible for generation of seizures in the rodent models of epilepsy we will use. We expect that such manipulation will suppress subsequent seizures. Our hypothesis views and treats epileptic seizures as a network function in the brain. Together with robust network-specific suppression of seizures in mouse models of epilepsy, this will change the way we view and treat this disease.

Project Summary Tobacco smoking is one of the most preventable causes of morbidity and mortality worldwide and has become a growing epidemic in developing countries in Africa. Among HIV+ individuals on antiretroviral therapy, smoking causes more life-year loss than HIV infection. While both behavioral approaches and pharmacotherapy are typically used together in high income countries, pharmacotherapy is largely unavailable in sub-Saharan Africa due to cost. Instead, developing and evaluating behavioral smoking cessation interventions, which could be realistically disseminated is a priority for addressing tobacco use among persons with HIV in countries such as Botswana. Yet, unique aspects of HIV (e.g., high rate of depressive symptoms) and delivery of care in such settings (e.g., decentralized, limited infrastructure) must be considered when designing a behavioral approach in LMICs such as Botswana. Depressive symptoms are common in HIV populations and often comorbid with smoking, and addressing depressive symptoms has been related to better smoking cessation rates. Behavioral activation therapy, rooted in a behavioral economics framework, has been effective at treating depression and preliminary data in the US, including in our group, suggests that it may effectively address smoking as well. Behavioral activation aims to increase engagement in healthy rewarding activities (i.e., substitute reinforcers) by reducing patterns of avoidance, withdrawal, and inactivity, and decrease activities that enhance the rewarding aspects of smoking (i.e., complementary reinforcers). In a parallel way, problem solving approaches have been used with HIV populations for behavior change regarding medication adherence, have also been successful at decreasing depressive symptoms, and are ideally suited for helping smokers select and implement personalized behavioral activation activities to quit smoking. We therefore created the novel Behavioral Activation/Problem Solving for Smoking Cessation (BAPS-SC), culturally adapted it and pilot tested it in Botswana and found it to be feasible and appealing and to have preliminary evidence of efficacy. We will conduct a 1:1 randomized trial comparing a BAPS-SC with standard counseling for smoking cessation in 650 HIV+ smokers in Botswana. We will leverage HIV care sites and deliver the interventions by phone to extend the reach of skilled practitioners. We will also assess whether depressive symptoms moderate the effect of BAPS-SC and test our proposed mediating pathways for the interventions' effects This project will determine whether the novel intervention is superior to standard counseling to establish a new paradigm for LMIC smoking cessation programs. We will also further our understanding of whether depressive symptoms, reinforcers, and problem solving are modifiable mediators of smoking. Leveraging the HIV care infrastructure will facilitate scale-up in sub-Saharan African settings where HIV is common and smoking continues to emerge as a threat to HIV+ individuals' health and survival.

Project Summary/Abstract To achieve aspirational goals to end the HIV epidemic (EHE), evidence-based practices (EBPs) to increase viral suppression must be implemented effectively nationally. The Managed Problem Solving (MAPS) behavioral intervention is an EBP for behavior change in people living with HIV (PLWH). To accomplish the goals of this application, we leverage a data-to-care partnership between the Philadelphia Department of Public Health (PDPH) and participating clinics (n = 12), which enhances the sustainability of our approach. We propose that MAPS can be delivered by trained Community Health Workers (CHWs). The use of CHWs to deliver MAPS is justified by their ability to develop trusting relationships with their clients and the need for task shifting in busy clinics. In order to also address retention in care, we will adapt MAPS to also focus on problem solving activities tailored toward retention in care (now termed MAPS+). CHWs will be located in clinics to implement MAPS+ to improve viral suppression and care retention in PLWH. Data-to-care allows for identification of people who are lost to care and link these patients back to care. Currently, medication adherence and retention in HIV care are not targeted in data-to-care so we will build on this approach to facilitate the identification of PLWH who are out of care and not virally suppressed to offer them MAPS+. Our set of implementation strategies include task- shifting the delivery of MAPS+ to CHWs, providing the CHWs training and ongoing support, and increasing communication between the CHWs and medical care team via standardized protocols. We will conduct a hybrid type II effectiveness-implementation trial with a stepped-wedge cluster randomized design in 12 clinics to test MAPS+ compared to usual care using a set of implementation strategies that we believe will best support implementation. Each clinic will be randomized to one of three implementation start times. We will collect baseline (usual care) data from each clinic for 6 months, followed by MAPS+ and our package of implementation strategies for 12 months, in three cohorts of 4 clinics each. Aim 1 will test the effectiveness of MAPS+ on clinical effectiveness outcomes, including viral suppression (primary) and retention (secondary). Aim 2 will examine the effect of the package of implementation strategies on reach. We will also measure implementation cost. Aim 3 will apply a qualitative approach to understand processes, mechanisms, and sustainment of our implementation approach. Our results will guide future efforts to implement behavioral EBPs across the HIV care continuum, consistent with the ?treat? pillar of EHE, and move the science of implementation services, consistent with NIH strategic priorities.