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NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT People living with Human Immunodeficiency virus (HIV) are up to 20 times more likely to develop active tuberculosis (TB) than people without HIV (PWoH). While anti-retroviral therapy (ART) has increased their health and lifespan, people with HIV (PWH) on ART are still at 4-5 fold greater risk for developing TB following infection with Mycobacterium tuberculosis (Mtb) compared to people without HIV (PWoH). However, why viral suppression and CD4 reconstitution following ART do not fully abrogate the risk of TB remains unclear. Residual inflammation present in PWH on ART has been linked to increased risk of co-infections and comorbidities. In addition, several lines of evidence show that PWH on ART have alterations in cellular metabolism, mainly within myeloid compartments, suggesting compromised abilities to mount effective immune responses to pathogens. A population of immunosuppressive cells termed myeloid-derived suppressor cells (MDSCs) has been implicated in dysfunctional immunity to HIV and Mtb infection. MDSCs were first described in cancer as negatively regulating tumor environments and suppressing NK and T cell functions. Higher frequencies of monocytic MDSCs (M- MDSC) were reported in PWH compared to PWoH, and M-MDSCs have been shown to expand after interruption of ART. Interestingly, M-MDSCs are also induced following Mtb infection but their role in anti-TB imunity in PWH on ART are not understood. We hypothesize that M-MDSCs suppress T cell functions and promote dysregulated immunometabolic responses to Mtb in PWH on ART. We propose to leverage bio-banked cryopreserved PBMC samples available through the Emory Center for AIDS research (CFAR) and our own archived samples, including from people with active and latent TB, with and without HIV. In Aim 1 we will employ multi-omic and immunologic approaches to derive an integrated MDSC biosignature associated with their suppressive functions and evaluate MDSC signature and frequencies in ART-naïve PWH, PWH on ART and PWoH. In Aim 2 we will test the hypothesis that expansion of M-MDSCs in PWH on ART contributes to ineffective immunity against Mtb-infection and promotes immunometabolic dysregulation. Our studies will bridge major knowledge gaps and provide a framework for targeting MDSCs to improve ART and advance HIV cure.

NIA - National Institute on Aging

PROJECT SUMMARY Pelvic organ prolapse (POP) is an age-related disorder that affects up to 50% of women impacting quality of life and resulting in exorbitant healthcare costs. On a cellular level, the process of aging is termed cellular senescence and it has been associated with degenerative and age-related diseases. Despite current studies suggesting a link between POP and cellular senescence there is a lack of understanding of how senescence- associated changes contribute to the development of prolapse. In this application we will test the hypothesis that induction of cell senescence culminates in POP during aging. To accomplish this, we will use state-of-the art methodologies (single-cell and single-nuclei RNA sequencing; biomechanical phenotyping considering both contractile and non-contractile properties) to reveal new facets of cell senescence signaling pathways in the vagina with age and known development of prolapse. We will employ a translational approach that combines both human research and animal models, which will allow for longitudinal follow-up that is not feasible in humans. Our specific aims are to (1) identify the differential gene expression and extracellular matrix regulation of age- related POP using an animal model, (2) determine if vaginal contractile potential and biomechanical stability are rescued in a novel mouse model of prolapse and cellular senescence, and (3) link extracellular matrix composition with cell senescence in vaginal stromal tissues from women with and without prolapse. The research proposed here will help define the mechanism of cell senescence in initiating the path of loss of pelvic organ support during aging. Identification of cellular pathways and unique cell populations associated with the development of prolapse can result in the design of interventional strategies that can prevent or slow the progression of cell senescence and in turn prevent development of POP. Successful execution of the aims of the proposed study will transform pelvic floor medicine and inform other aspects of the biology of aging.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Antiretroviral therapy (ART) effectively suppresses HIV replication but fails to eliminate the viral reservoir—a heterogeneous population of infected cells that persist despite treatment. While most proviruses are defective, many retain the ability to express RNA, proteins, and even viral particles, contributing to persistent viremia, chronic immune activation, and complicating the interpretation of viral load measurements. Among these, proviruses with defects in the 5’ leader (5’L) region are common, and they decay more slowly than intact proviruses, are translation-competent, and are often implicated in persistent non-suppressible viremia (NSV), making them a critical component of HIV persistence and a significant source of residual antigenic stimulation. The long-term goal of this project is to define the mechanisms by which 5’L-defective proviruses evade negative selection, characterize their contribution to persistent viremia, and determine their impact on HIV-specific immune responses. Our central hypothesis is that 5’L-defective proviruses retain the ability to express viral genes while evading immune-mediated killing and cytopathic effects. To test this, we will (1) apply a novel digital PCR assay that distinguishes intact from 5’L-defective RNA without requiring sequencing to quantify their contribution of defective proviruses to plasma HIV RNA; (2) isolate and phenotype clonally expanded CD4+ T cells harboring 5’L-defective proviruses using two complementary approaches—stimulation with Tat-LNP followed by p24+ cell sorting, and limiting dilution culture ex vivo—to assess viral transcription and translation through multi-omic analyses (SMARTseq, Ribo-seq); (3) investigate susceptibility of 5’L defective proviruses to HIV-specific CTL, and leverage longitudinal samples from individuals with NSV to evaluate how antigen expression from defective proviruses shapes HIV-specific immune responses and clonotype dynamics over time. This research is innovative in developing a first-in-class assay to parse 5’L-defective RNA without sequencing and applying cutting-edge single-cell and immunologic profiling to study the interplay between defective proviral expression and host immunity. The proposed research is significant because it is expected to address critical gaps in our understanding of HIV persistence, improve the interpretation of HIV cure clinical trials, and inform new strategies aimed at targeting cells with intact and defective proviruses. Ultimately, this project has the potential to offer new tools to improve the clinical outcome of people living with HIV and opportunities for the development of innovative strategies to achieve HIV remission.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Significance: Providing antiretroviral therapy (ART) to pregnant women with HIV (WHIV) is a landmark global public health achievement, preventing millions of perinatal HIV infections. However, there are now >1 million children exposed to antiretrovirals (ARVs) born annually, a number expected to stabilize or increase over the next decade as WHIV and women exposed to HIV during conception and pregnancy are increasingly taking ARVs as treatment or prophylaxis against HIV (PrEP). To date, the effects and safety of ARVs taken in pregnancy are not fully established and prior research is limited by lack of objective measurement of ARV exposure, and data are lacking on the effects of ARVs on the placenta. Thus, there is a critical gap in knowledge about the impact of ARVs, including PrEP, and association with objective drug levels taken in pregnancy on the placenta and fetus, information needed for optimal ARV design and to advise women on the effects of ARVs taken as treatment or prevention during pregnancy to inform risk-benefit discussions. Innovation: We propose one of the first studies to simultaneously measure ARV levels in dried blood spots from pregnant women and their children’s hair to quantify drug exposure to PrEP and ART in utero and relate ARV levels to placental findings and birth weight. Distinct advantages of our proposed research over prior studies include 1) simultaneous collection and comparison of placentas from WHIV taking ART, HIV-uninfected women taking ARVs as PrEP, and HIV- uninfected women taking no ARVs, and 2) prospective enrollment and observation of pregnant women and children from these three groups to minimize bias, enhance rigor and reproducibility, and relate placental and birth outcomes to in utero exposures. Investigator team: PI Bebell has expertise in HIV epidemiology in pregnancy and placental effects. Co-I Ngonzi has expertise with HIV and pregnancy outcomes in Uganda. Biostatistician Correia has expertise in analyzing data from observational maternal-child outcomes studies in HIV-affected populations and mediation analysis. Approach: We will leverage stored dried blood spot and hair samples from the PI’s ongoing NIH-funded (R01HD112302) PACO cohort in Uganda, clinical and placental histopathology data from enrolled women and their children, established laboratory infrastructure at UCSF’s Hair Analytical Laboratory and AHRI’s pharmacology laboratory to elucidate the independent effects of HIV and ARV exposure on the placenta and birth weight through these Specific Aims: 1) Compare histologic placental abnormalities by ARV levels in neonatal hair and maternal DBS, and 2) Determine the effects of ARV exposure on birth weight and whether placental abnormalities mediate these effects. Determining the impact of ARVs in pregnancy on the placenta and birth weight and the possible mediating role of the placenta has great potential to improve child health through optimizing outcomes and inform choices for women accessing ARVs as treatment and prevention during pregnancy. By leveraging already-collected samples and data from an NIH-funded study, this proposal will inform practical strategies to improve ARV-related outcomes.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

Project Summary Highly effective antiretroviral therapy (ART) has significantly reduced the mother-to-child transmission of HIV but has also increased the number of children who are HIV exposed uninfected (HEU) and exposed to ART during gestation. Current national and international ART prescription guidelines now recommend maternal use of integrase strand transfer inhibitor (InSTI)–based regimens throughout pregnancy. Importantly, while InSTI use is associated with fat tissue expansion and impaired bone mass in adults and adolescence with HIV, the consequences of in utero exposure to InSTIs on offspring fat and bone development remain unknown. A key barrier to our understanding of these effects is the recent adoption of InSTI use during pregnancy, which limits the number and age of children exposed to InSTIs available for study. Therefore, to address this gap, our laboratory utilized a preclinical mouse model of gestational exposure to maternal InSTI-based ART and found long-lasting changes in offspring weight and bone length, suggesting that early InSTI exposure can disrupt normal developmental pathways. Building on these findings, the proposed study will investigate the mechanisms underlying impaired fat and bone development following exposure to maternal InSTI-based regimens. Due to the early exposure and the long-lasting tissue changes, we hypothesize that maternal and lactation exposure to InSTI-based ART causes epigenetic alterations associated with adverse fat and bone development in HEU children. To test our hypothesis, we will use our preclinical mouse model to investigate the longitudinal impact of various InSTI-containing regimens on key offspring development stages and evaluate the tissue level mechanisms, including epigenetic changes, associated with structural (mass) changes. To ensure clinical relevance, we will also leverage data and samples from the Pediatric HIV/AIDS Cohort Study (PHACS) and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) to evaluate whether epigenetic changes in HEU children differ between InSTI-based and InSTI-sparing regimens and are dependent upon the antiretrovirals used in combination with InSTIs. If successful, results from this proposal will inform safer ART prescribing during pregnancy and guide strategies to optimize lifelong health among children exposed to HIV and ART in utero.

NIEHS - National Institute of Environmental Health Sciences

PROJECT SUMMARY Micro- and nanoplastics (MNPs) are emerging as a ubiquitous and persistent environmental contaminant. Human exposure to MNPs is widespread, with ingestion being the main exposure route. Research addressing the potential impact of MNPs on human health is urgently needed. MNPs can reach and accumulate in the heart. However, the impact of MNPs on the heart is very poorly understood. Notably, a recent epidemiologic study has shown that higher exposure to MNPs is associated with increased cardiovascular events in human patients. This new evidence highlights the potential cardiovascular toxicity of MNPs in humans and the critical need to understand the effects of MNPs exposure on the heart. In preliminary studies in human inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and/or rats, we found that exposure to MNPs caused cardiac toxicity including reduced cardiac myocyte viability, increased reactive oxygen species (ROS), and decreased left ventricular mass. Remarkably, in rat exposure studies, we found that MPNs exposure significantly increased myocardial infarction size and cardiac tissue damage following cardiac ischemia injury. Supported by compelling preliminary results, we propose to address the central hypothesis that exposure to environmental MNPs causes mitochondrial dysfunction and oxidative stress in the heart, leading to increased susceptibility of the heart to damage; such cardiac toxicity is manifested as worsened infarction and heart dysfunction following ischemia injury (ie, heart attack). The proposed study will be carried out by an interdisciplinary team that comprises researchers in cardiac toxicology, chemistry, clinical cardiology, and biostatistics. The study uses both an in vivo rat model and human iPSC-derived cardiomyocytes and human cardiac organoid models, and are of strong relevance to human heart health. Importantly, taking advantage of our breakthroughs in producing “true-to-life” MNPs that mimic real-life environmental MNPs, we will use such “true-to-life” MNPs in the entire study, making the study highly relevant to real-life environmental MNPs exposure. In whole animal exposure studies, internal MNPs exposure levels and tissue distribution will be analyzed using state-of-the-art analytical chemistry approaches. Three aims are proposed. Aim 1 examines the impact of MNPs on cardiac physiology and function; Aim 2 addresses the impact of MNPs on cardiac damage and adverse outcomes following ischemia injury; Aim 3 examines the mechanism underlying MNPs-induced cardiac toxicity, focusing on the autophagy-lysosome pathway and mitochondria dysfunction. The proposed studies are significant because they are expected to provide critical knowledge on MNPs-induced cardiac toxicity in human-relevant experimental models, thus having strong environmental health significance. Further, the studies will contribute to our recognition of the role of MNPs in affecting the outcomes of heart attack - a top cause of death and morbidity in the US, thus having strong clinical and translational impact.

NIDA - National Institute on Drug Abuse

Use of antiretroviral therapy (ART) has considerably increased life expectancy for people with HIV (PWH) resulting in increased risk of age-related non-AIDS-defining health burden, including inflammaging, a low-grade chronic proinflammatory immune response, among the older population of PWH compared to the general population. A large proportion of PWH are often found to be addicted to synthetic or non-synthetic opioids, resulting in opioid use disorder (OUD), which can also add to proinflammatory immune response. However, little is known about the consequences of long-term ART and OUD on inflammaging in this aging PWH. Interestingly, a common denominator for aging, HIV and OUD is that they all cause mitochondrial dysfunction in immune cells as indicated by various previous reports. Mitochondria are highly dynamic organelles, essential for cellular metabolism, stress responses and homeostasis maintenance and are considered as the hub for biochemical processes including oxidative phosphorylation (oxphos), adenosine triphosphate (ATP) production, intracellular reactive oxygen species (ROS) generation, fatty acid synthesis and calcium (Ca2+) homeostasis. Our previously published data have shown that mitochondrial ROS increased with mitochondrial depolarization in people with HIV. Moreover, our exciting preliminary data indicated that mitochondrial ROS in immune cells is further increased in older PWH with age ≥50years compared to younger PWH with age <50 years. In addition, PWH with OUD had more mitochondrial ROS+ and reduced mitochondrial membrane potential in immune cells compared to PWH without OUD. Also, we found increased inflammatory immune markers in plasma of PWH with OUD. In view of this evidence, we hypothesize that OUD aggravates inflammatory immune response by increased mitochondrial dysfunctions in aging PWH. To test our hypothesis, we propose to evaluate the extent of OUD induced mitochondrial dysfunction in aging PWH, by studying mitochondrial mass, mitochondrial superoxide levels, mitochondrial membrane potential, mitochondrial fusion/fission, mitophagy, expression of mitochondrial stress response genes, oxidative phosphorylation and mitochondrial NADH levels in peripheral blood mononuclear cells (PBMC) of ART-treated PWH of age ≥50years, with or without OUD. In addition, we will identify cell specific molecular targets contributing to mitochondrial dysfunction, cellular senescence and inflammaging in PWH with OUD by transcriptomic analysis using single cell RNAseq. Finally, we will investigate if treatment with ROS a scavenger or a NAD+ booster can improve mitochondrial function in immune cells and reduce proinflammatory immune response in aging PWH with OUD. This proposal aims to advance the foundational knowledge about the role of mitochondria in the age-related altered immune cell function in older ART receiving PWH with OUD, which could be leveraged to develop targeted therapies and improve outcomes in people aging with HIV, opioid use and addiction.

NIA - National Institute on Aging

PROJECT SUMMARY/ABSTRACT Epidemiological evidence links peripheral inflammation to an increased risk of dementia, yet the mechanisms underlying this association remain unclear. Although peripheral immune challenges can amplify neuroinflammation and accelerate cognitive decline, we still do not understand the thresholds required to elicit neuroinflammatory responses that alter neuronal activity, their underlying cellular mechanisms, or how these thresholds and mechanisms change with age. This gap stems from viewing neurons as a passive recipient of neuroinflammatory signals, but also from the use of models with limited relevance. Our long-term goal is to understand how peripheral inflammation interacts with aging to increase the risk of dementia. Prior studies showed that aging sensitizes microglia, making them highly responsive to immune signals and driving exaggerated responses that disrupt synaptic circuits and lead to cognitive deficits. Furthermore, increasing evidence-including our preliminary data-indicates that peripheral inflammation can also directly alter neuronal activity and connectivity. Our proposal builds on this foundation and advances a novel hypothesis: while chronic inflammation directly activates microglia, in acute inflammation, the flow of events begins with neurons. Our preliminary data show that acute inflammation initially alters the activity of inhibitory neurons in key cortical regions. This change may then be detected by microglia, which respond according to their current, age-dependent state by further altering inhibitory synapses and the excitation-inhibition balance. To test this hypothesis, we will use mouse models that mimic common human inflammatory conditions: house dust mite (HDM}-induced respiratory allergy and dextran sulfate sodium (DSS}-induced colitis. Aim 1 will define microglia responses to acute and chronic inflammation as a function of age and will assess whether T cells contribute to increased responses of microglia to acute inflammation in aged mice. Aim 2 will test whether changes in inhibitory activity following acute inflammation trigger microglia activation in aged mice and will define the associated microglial molecular responses. Aim 3 will examine if microglia respond to changes in inhibitory activity by further altering cortical circuits in an age-specific manner. With expertise in molecular, cellular, and circuit neuroscience, inflammation, and imaging, our team is uniquely positioned to carry out this interdisciplinary project. The Pl's past discovery of specific microglia-inhibitory neuron interactions is an additional strength. We will use an innovative approach that combines relevant mouse models, advanced immunological techniques (e.g., adoptive transfer, immune cell depletion), and state-of-the-art neuroscience methods (e.g., calcium imaging, chemogenetics) to test our hypothesis. This research addresses a significant biomedical challenge-understanding how peripheral inflammation affects the aging brain-and has the potential to transform our understanding of neuroimmune interactions in dementia. We will identify key features of microglia-PV neuron interactions following peripheral inflammation and define how they shift with aging. Ultimately, our findings could reveal age-specific therapeutic strategies to reduce the risk of dementia.

NIDA - National Institute on Drug Abuse

HIV infection and nicotine addiction are significant global health issues, particularly among young adults, with increasing co-occurrence. Despite successful antiretroviral therapy (ART), 30–60% of people living with HIV (PLWH) develop HIV-associated neurocognitive disorders (HAND). Nicotine negatively impacts HIV⁺ individuals, potentially contributing to disease progression by facilitating neuroinvasion through CD4⁺ T cells that cross the blood-brain barrier (BBB). These cells, once in the central nervous system (CNS), release neurotoxic particles and inflammatory cytokines, leading to synaptic damage. Chronic nicotine activates nicotinic acetylcholine receptors (nAChRs) on T cells, enhancing their proliferation and cytokine release. Our hypothesis is that chronic nicotine enhances HIV⁺ CD4⁺ T cell neuroinvasion through convergent chemotactic signaling involving HIV gp120 and nicotine receptor activation. We will test this hypothesis through three aims. Aim 1 is to investigate how HIV infection promotes chemotaxic signaling in CD4⁺ T cell neuroinvasion, utilizing an in vitro BBB transmigration assay and measuring the phosphorylation of cytoskeletal regulators. Aim 2 is to assess chronic nicotine's effects on HIV⁺ CD4⁺ T cell proliferation and pro-inflammatory responses, focusing on nAChR expression and activation of chemotactic signaling pathways. Aim 3 is to evaluate the effects of chronic nicotine and HIV infection on CD4⁺ T cell behavior in an HIV humanized mouse model, monitoring inflammatory cytokines, viral reservoirs, and neuroinvasion in brain regions susceptible to T cell infiltration. This study is proposed by a strong team of co-PIs with complementary expertise in HIV signaling, nicotine research, T cell immunology, and drug abuse animal models, ensuring a comprehensive approach to understanding the interplay between HIV and nicotine addiction in neuroinvasion.

NIAID - National Institute of Allergy and Infectious Diseases

Project Abstract: Significant advances in antiretroviral therapy (ART) has enabled functional suppression of HIV, allowing individual individuals on ART to live relatively normal lives. However, viral rebound from a persistent reservoir of provirus-harboring cells following ART cessation demands a lifelong reliance on ART. ART-free control of this persistent reservoir therefore represents the current focus of HIV cure strategies. Recent work from our group and others has identified HIV-infected CD4 T cells that exhibit cell-intrinsic resistance to CD8 cytotoxicity, despite antigen expression and recognition. While identification of resistance factors previously annotated in cancer (such as overexpression of the granzyme inhibitor SERPINB9 and the anti-apoptotic protein BCL-2) has provided some insight concerning underlying mechanisms, the factors leading to this resistance phenotype remain largely unknown. To address this, we have developed a novel genome-wide screening platform that allows identification of genes involved in primary human CD4 T cell resistance and susceptibility to CD8 T cell cytotoxicity. In this proposal, we aim to maximize the potential of this newly developed CD4 resistance screening model (CRSM). Additional screens in different contexts will be conducted to further enrich the dataset. We will also employ a methodical pipeline for hit validation and therapeutic characterization. This pipeline will begin with promising hits identified in the initial screen, including the lipid metabolism-associated PPAR family proteins. This proposal will produce a robust functional genomic dataset thoroughly characterizing the mechanisms underlying CD4 resistance to CD8 killing. With these datasets, we envision the nomination of a range of promising targets for small-molecule sensitization of HIV-infected CD4s to CD8 killing.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Despite major advances in antiretroviral therapy (ART) treatment and distribution, latently infected “reservoir” cells remain a major barrier to developing a cure for human immunodeficiency virus (HIV) infections. Replication- competent HIV reservoirs are rare and remain stable for decades during ART, providing opportunities for viral rebound in the absence of ART. Multiple strategies have been explored in the field to eliminate or permanently silence HIV reservoirs, including the “kick and kill” cure approach. This two-pronged approach consists of inducing HIV reactivation from latency (kick) using a latency reversing agent (LRA), enabling a subsequent “kill” through immune mechanisms or viral cytopathic effects. However, no LRAs that completely reactivate all latent HIV have been identified, and the most successful introduce potentially harmful side effects such as proinflammatory cytokine induction. Thus, there remains a need to not only identify improved LRAs that balance HIV reactivation and immune activation, but also develop a greater understanding of the pathways involved in maintaining HIV latency. In this project, we propose to improve “kick and kill” LRAs through two approaches. Previous studies demonstrate protein kinase C modulators (PKC) are a particularly potent LRA class that strongly reverse HIV from latency but simultaneously induce high levels of proinflammatory cytokines upon activating T cells. Synthesized analogs of the natural PKC modulator bryostatin-1 have also been shown to possess improved tolerability and in vivo HIV reservoir reduction, highlighting the potential of optimizing compounds for the “kick and kill” approach. Building upon this, in Aim 1, we will evaluate promising next- generation PKC modulators for in vitro and in vivo latency reversal. To explore new molecular mechanisms of HIV latency, we propose to evaluate a novel polyadenylation-driven pathway using JTE-607, a small molecule with anti-inflammatory effects. In Aim 2, we will evaluate JTE-607 as a HIV LRA in vitro and in vivo and to complement strong but inflammatory PKC modulators by downregulating proinflammatory cytokine expression. By designing and working on this project, I will contribute enhanced LRAs that advance the “kick and kill” approach towards wider, safer implementation while enhancing fundamental knowledge of HIV gene regulation. Simultaneously, when completed, this project will yield improved HIV reservoir depletion strategies, complementing other cure approaches and bringing the field closer to a definitive HIV cure.

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NIMH - National Institute of Mental Health

PROJECT SUMMARY Stable HIV reservoirs remain a significant challenge for the eradication of HIV-1 (HIV). While several anti- HIV latency strategies have been proposed to control HIV reservoirs, few have proven effective in reducing the size of the HIV reservoir in clinical settings. This suggests that our current understanding of how HIV achieves its persistent infection is limited and underscores the need for the development of alternative innovative tools for HIV cure. Recently, we and others characterized a unique integrated stress response (ISR)/ATF4 signaling pathway that is essential for HIV transcription and early seeding of HIV. Conversely, when ATF4 is knocked down, HIV transcription is inhibited. We further defined ATF4 as a new transcription factor of HIV, exploited by HIV for its own transcription after the recruitment of ATF4 to the ATF/CREB consensus site at the 5’ HIV long-terminal repeat. ATF4 induction leads to HIV activation from latency, indicating that ISR/ATF4 signaling activation promotes HIV transcription while the suppression of ISR signaling is associated with the establishment of HIV latency. Of note, prolonged activation of ISR/ATF4 signaling also induces cell death, mediated by ATF4 binding to the promoter of the CHOP gene, an essential protein driving apoptosis during persistent ISR/ATF4 activation. In a primary CD4+ T cell model of latency, prolonged ISR/ATF4 signaling activation disrupts latent HIV and selectively induces apoptosis in HIV+ CD4+ T cells, without affecting bystander HIV-negative CD4+ T cells. Notably, using viral outgrowth assays, we discovered that prolonged ISR/ATF4 signaling activation reduces replication-competent HIV by up to 2,300-fold in resting CD4+ T cells isolated from people with HIV receiving suppressive antiretroviral therapy (ART). Therefore, we hypothesize that the suppression of ISR/ATF4 signaling is essential for HIV persistence. This will be tested through three specific aims: Aim 1: Investigate how activation of the ISR/ATF4 signaling pathway eliminates HIV-latently infected T cells and brain microglia. Aim 2: Elucidate the unique mechanisms by which ISR/ATF4 signaling controls the stable HIV reservoir for the establishment of HIV latency. Aim 3: Determine the effectiveness of activating ISR/ATF4 signaling in eliminating HIV reservoirs in the hu-BLT mouse model of HIV latency in vivo.

NCI - National Cancer Institute

PROJECT SUMMARY Obesity is a risk and progression factor for ≥13 cancers including, including endometrial cancer (EC, the most common obesity-related cancer in women), and colorectal cancer (CC, the most common obesity-related cancer in men). Incretin mimetics, which are agonists at one or more satiety-related receptors, can induce sustained weight loss. Limited epidemiological and preclinical data on these medications suggest potential for preventing obesity-related cancers, albeit via unclear mechanisms. We propose to test the novel central hypothesis that incretin mimetics offer protection from common obesity-related cancers via interacting mechanisms involving direct effects on CD8+ T cells as well as systemic effects on diet-regulated hormones, particularly leptin. We will leverage rigorous, complementary lines of research (preclinical models of obesityassociated cancers and a medically supervised human weight loss cohort) with state-of-the-art approaches, robust informatics data integration, and an accomplished transdisciplinary team to (a) identify immunologic, molecular, metabolic and anticancer effects of semaglutide v tirzepatide, 2 FDA-approved incretin mimetics for weight loss that differ in their anti-obesity effectiveness, across mouse models of EC and CC; (b) extend in multiple preclinical models our preliminary finding that CD8+ T cells play a central mechanistic role in TZP’s anticancer effects; and (c) establish concordance of incretin mimetic-associated anticancer effects between mouse models and women at high risk for EC undergoing medically supervised weight loss. Three specific aims are proposed to test our hypothesis: 1. Determine the effects of SEM v TZP v vehicle on phenotypic, immunologic, and molecular features and tumor outcomes in mouse models of obesity-driven EC and CC; 2. Establish the interacting roles of CD8+ T cells and leptin in SEM v TZP’s anticancer effects in models of EC and CC; and 3. Determine the effects of SEM and TZP on phenotypic and molecular features systemically and in the uterus of women at risk of EC undergoing medically supervised weight loss. The proposed studies in mice and humans will clarify whether, and how, 2 incretin mimetics, differing in their receptor targets and antiobesity effectiveness, inhibit EC development and progression in individuals. The proposed studies propose the use of vertebrate animal models in parallel with human studies because the mechanistic effects of incretin mimetics on obesity-associated tumor development, systemic metabolism, leptin signaling, and CD8⁺ T-cellmediated immunity cannot be adequately interrogated in humans alone, or replicated using non-animal systems such as cell culture or organoids. Mouse models are essential to enable controlled manipulation of diet, obesity status, pharmacologic exposure, and longitudinal tissue analyses across the full course of tumorigenesis, while also providing translationally relevant physiologic and immune responses that closely parallel those observed in humans.

Indiana Arts Commission

Indiana Arts Commission provides grants to support arts and cultural programming, artist fellowships, arts education, and community-based arts projects across IN.

Infosys Foundation

100M+ USD/yr supporting education, healthcare, rural development, and arts in India.

Inland Empire Community Foundation

Inland Empire Community Foundation ($200M in assets) supports nonprofits in CA through grants focused on education, health, arts, community development. Awards range from $2,000 to $75,000.

NEI - National Eye Institute

SUMMARY Alpha herpesviruses are a subfamily of ubiquitous viruses that can cause a spectrum of clinically-significant diseases including blindness from acute retinal necrosis (ARN). Unfortunately, even with timely antiviral treatment, irreversible pathological changes occur within the retina and significantly increase the risk of vision- threatening complications to further compromise an already poor visual prognosis. Since the advent of acyclovir, there have been no major advances in the treatment of clinically-significant herpes infections despite the vision-degrading complications and very little is known in regards to the immune response to the virus within the retina. This proposal will provide a fundamental understanding of the innate immune response to HSV-1 within the retina, while developing critical skills in career development. The long-term goal of this project is to acquire the scientific skills needed to enhance our understanding and pursue novel therapies to preserve vision and reduce complications related to ARN as an independent clinician-scientist. The scientific objective of this K08 proposal is to test the hypothesis that type I interferons (IFNs) are central to host defense to viral infection of the retina and that toll-like receptor-3 within retinal microglia activate this innate immune response. We propose evaluating the innate immune response to herpes virus infections of the retina by utilizing several immune knock-out mouse lines, human retinal cell cultures, and vitreous specimens from patients with ARN to assess the role of IFNs and their role in neuroinflammation. Three focused specific aims will be utilized to test our hypothesis: 1) Identify pathways and cell types responsible for HSV innate immunity within the retina; 2) Determine the role of downstream IFNs in host defense against viral infection of the retina; 3) Identify the predominate IFN subtype and cellular source in acute retinal necrosis from human samples. The career development objective is to develop the mentorship and expertise needed to become a productive and independent clinician-scientist. The Department of Ophthalmology and Visual Sciences and the University of Nebraska Medical Center have state-of-the-art laboratory facilities and world-class faculty with expertise in neuroimmunology, viral infections, and innate immune signaling to serve as the mentoring team. The institutional resources, mentorship team, and career development plan have been developed to specifically promote scientific independence in the study of neuroinflammation of the retina.

Inner-City Muslim Action Network

Supports community organizing, health services, arts, and transitional housing on Chicago's South Side. Model for faith-based community development.

Innovia Foundation

Innovia Foundation ($200M in assets) supports nonprofits in WA through grants focused on education, community development, health, arts. Awards range from $1,000 to $50,000.

NCATS - National Center for Advancing Translational Sciences

PROJECT SUMMARY The Penn-CHOP Clinical and Translational Science Award (CTSA) Hub proposes a transformative vision to catalyze a dynamic clinical and translational science (CTS) ecosystem that accelerates the delivery of innovative, life-altering therapies to individuals across the lifespan. Aligned with the NCATS mission to bring more treatments to all people more quickly, our Hub will leverage its nationally-recognized strengths in translational therapeutics, data science, community engagement, and workforce development to advance the science and practice of clinical translation. We propose four integrated aims: (1) Innovate novel approaches to advancing the development and dissemination of translational therapeutics; (2) Accelerate the application of state-of-the-art data science resources and dynamic data ecosystems to enable a Penn-CHOP academic learning health system (aLHS) framework and catalyze groundbreaking CTS; (3) Integrate our Hub with our communities and stakeholders to promote community-partnered and collaborative research within families and across the lifespan; (4) Educate, train, advance, and retain a skilled multidisciplinary workforce ready to meet the demand of an ever-evolving CTS and and CTR landscape. Our Hub will serve as a national model for integrated, community-engaged, and data-driven translational science. Through rigorous evaluation, continuous quality improvement, and dissemination of best practices, we aim to contribute meaningfully to the CTSA consortium's collective impact on public health.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY First-ever data from Zambia on people who inject drugs (PWID) demonstrates major gaps in the HIV epidemic response. A recent biobehavioral survey show sharp health disparities along the entire PWID HIV care continuum, with gaps in HIV testing, linkage to ART, and viral suppression, and limited knowledge of PrEP. Failing to detect early HIV infections and address unsuppressed viral load poses a risk of ongoing community transmission as well as increased risk for HIV comorbidities and mortality, threatening the overall HIV epidemic control response in Zambia. The Zambia Ministry of Health has adopted a harm reduction approach to address the health disparities experienced by PWID. Starting in November 2024, the Zambia Ministry of Health will provide Medications for Opioid Use Disorder (MOUD) at two health facilities which also provide HIV services. There is currently minimal evidence in sub-Saharan Africa on MOUD integration with HIV care. The arrival of MOUD in Zamvia presents an exceptional opportunity to collaborate with Ministry of Health and key partners to develop a person-centered integrated collaborative care model for PWID and pilot testing implementation, feasibility, and preliminary effectiveness within the Zambian health system. We propose the Integrated Services for PWID using Person-centered Interactions, Reach, and Engagement (INSPIRE) study to co-adapt and evaluate an HIV status-neutral system-level integrated approach using a Collaborative Care Management Model (CoCM) for HIV prevention, HIV care, mental health, and MOUD. This implementation science study includes the following Aims: Aim 1: Assess the multilevel determinants of early implementation of MOUD services using rapid qualitative analysis. Aim 2: Co-adapt an HIV status-neutral CoCM with key stakeholders. Aim 3: Implement and evaluate the co-adapted CoCM, guided by Practical, Robust Implementation and Sustainability Model (PRISM), and including the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) outcomes. The research team, led by Multiple Principal Investigators (MPI), has expertise in psychiatry, HIV clinical care, implementation science, behavioral and social sciences, HIV clinical care, epidemiology, and mixed methods, and has a deep knowledge of HIV response and service delivery models in Zambia for marginalized populations, and experience implementing opioid use treatment both in the US, and in Kenya. We will also leverage the University of Maryland Baltimore’s decade of experience implementing MOUD and HIV programs in Kenya. Addressing the unmet needs of PWID is urgently needed to achieve and maintain HIV epidemic control; our findings will inform the implementation of integrated care models for PWID. Lessons learned from INSPIRE will help develop best practices for system-level approaches to improve OUD treatment and HIV prevention and treatment programs in both sub-Saharan Africa and the US.

NIDA - National Institute on Drug Abuse

Substance use disorder (SUD) is a leading public health challenge, with long-term consequences for physical and mental health. In-person peer support groups are well-established as beneficial for recovery. However, as digital platforms increasingly serve as spaces for peer support, little is known about how engagement in online peer support recovery groups is associated with recovery outcomes. Emerging research has yielded conflicting results, with some studies suggesting benefits while others indicating relapse risks. This underscores the need to examine the content of discussions beyond engagement frequency. The present application seeks support for Xiangyu Tao, Ph.D., a postdoctoral associate at the Rutgers Addiction Research Center, gain the necessary training and set up a line of research to examine the role of online peer support recovery communities in SUD recovery. Specifically, she will integrate state-of-the-art artificial intelligence (AI) techniques, including Large Language Models (LLMs), with co-production to identify communication patterns and to examine their associations with recovery outcomes. LLMs offer a promising avenue for analyzing large-scale online discussions, yet they require human oversight to address challenges such as contextual misinterpretation and ethical concerns. Co-production, i.e., involving individuals with SUD recovery experience in all research stages, mitigates LLM limitations and ensures that results reflect lived experience. The mentored K99 phase will identify and characterize communication patterns in online recovery groups. Peer support and co-rumination patterns will be classified using LLMs and co-production (Aim 1); latent class analysis (LCA) will identify distinct communication profiles among users engaging in these online groups (Aim 2). During this phase, Dr. Tao will receive mentorship in co-production and AI methodologies, longitudinal data analysis and management, and responsible AI research. The independent R00 phase will build upon this foundation by examining how communication profiles are associated with recovery trajectories using longitudinal survey data from online recovery group participants (Aim 3). This project is highly innovative in its integration of LLMs and co- production to analyze large-scale digital recovery discussions, ensuring that AI-driven insights are both computationally rigorous and socially informed. Findings will enhance understanding of digital peer support for SUD recovery and will inform future mechanistic studies and SUD interventions. By identifying communication patterns associated with recovery trajectories, this project will guide digital health platforms, peer support programs, and clinicians in optimizing online recovery environments to better support individuals with SUD. This project aligns with the NIDA Strategic Plan Cross-Cutting Priority to "Leverage Data Science and Analytics to Understand Real-World Complexity" by utilizing advanced computational methods to analyze digital recovery support interactions. The project is highly significant in bridging advanced AI computational tools with the lived experiences of individuals to produce impactful research to promote substance use recovery.

NIDA - National Institute on Drug Abuse

PROJECT ABSTRACT We seek to refine, field test, and deploy an intelligent AI-based chatbot in small, peer-to-peer mobile support groups for smoking cessation. The chatbot will complement the human support group members by responding to posts when no human can. We expect the chatbot to improve engagement by ensuring no post goes unanswered. By developing and testing this chatbot, we hope to breathe new life into research on mobile health support groups which have been challenged by low engagement. We have already built a chatbot using a state-of-the-art open-access LLM (large language model) and set it up on a local, dedicated, secure server. The LLM does not store data on the cloud and all posts are encrypted before server storage. We have trained our chatbot on 77400 posts from our past mobile support groups to accurately comprehend the 25 most common post types. We have developed 25 response libraries for the chatbot that contain over 1k responses developed from knowledge bases, e.g., it provides support for quitting, assists with study-provided NRT, and advises on coping with cravings and stress. Our chatbot intervention is based on the Supportive Accountability Model of Mobile Health. We expect the peers in the group to provide legitimate information that is relevant, trustworthy, and expert, and to form social bonds by being caring, nonjudgmental, and timely, increasing accountability and adherence. By adding a chatbot, we hope to provide additional legitimate information and social bonding. Aim 1 is to refine the chatbot using human-centered design methods. Before putting the chatbot into groups, we want to ensure it can communicate 1:1. We will recruit 4 groups of 5 smokers (N=20), and ask each person to interact with the chatbot, using all 25 post types. They will think aloud in the presence of trained staff to identify and solve usage problems. The sessions will be taped, a survey conducted, and usability metrics assessed. Aim 2 to conduct a one-armed field trial to assess the chatbot’s feasibility and acceptability within human support groups. We will recruit smokers in 2 groups of 10 (N=20). Participants will be placed in a mobile group with the chatbot and asked to support each other in quitting for 2 weeks. We will download and analyze posts and conduct exit interviews. Aim 3 is to conduct a pilot RCT of chatbot efficacy. We will recruit 4 cohorts with 30 smokers per cohort, randomizing 15 smokers to intervention arm (support group with chatbot) and 15 to control arm (support group without chatbot). We will measure primary and secondary engagement outcomes and will have adequate power to compare intervention vs. control. We will also measure intervention-end bioconfirmed abstinence to power a larger RCT.