About the HNRC

The HNRC is organized as a set of Scientific Cores and a Developmental Core, with the work of these entities being harmonized by an Administrative Core. The Scientific Cores were chosen to provide the techniques and resources necessary for the next generation of neuroAIDS research. They include Cores in NeuroMedical, NeuroBehavioral and Psychiatry, Microbiome, and NeuroVirology and Biology.

The NeuroMedical Core will aim to: 1) Evaluate the impact on mental health outcomes (e.g., depression, neurobehavioral phenotypes) of HIV infection and comorbid conditions (e.g. insulin resistance, metabolic syndrome), coinfections (e.g. CMV, latent toxoplasmosis), antiretroviral therapy (ART) neuroprotection or neurotoxicity, and inflammation (e.g., cytokines, T-cell activation); 2) Evaluate the reciprocal effects over time, of mental health factors (e.g. apathy, stress, resilience, self-efficacy) and cognition, and downstream effects of these neurobehavioral factors on neuromedical and HIV disease outcomes (e.g. virologic suppression, healthcare engagement); 3) Support studies of the central nervous system (CNS) impact of interventions designed to alter HIV reservoirs and achieve functional cure, and treatment of latent or clinically asymptomatic coinfections; and 4) Evaluate how the microbiome influences inflammation, microbial production of neurotransmitters (e.g., serotonin) and in turn, neurobehavioral phenotypes including depression and cognition, as well as circadian rhythms, sleep, and social functioning. Standard evaluations will continue to include a structured neuromedical history, clinical and laboratory examinations, and establishment of diagnoses of central and peripheral neurological complications. Additional unique services of the Core include stool collection for gut microbiome characterization and lumbar puncture for cerebrospinal fluid (CSF) collection. The Lab Unit will perform blood and CSF biomarker assays and provide expertise in their analysis and interpretation. The NI Portal will provide resources (e.g., training, consultation, technical support) in support of studies investigating the underlying neural mechanisms of mental health disorders in the context of HIV using a broad array of techniques (e.g., structural, functional, and metabolite MRI, PET imaging).

The NeuroBehavioral and Psychiatry Core will contribute to the identification of individuals who have evidenced changes in cognition, depression and daily functioning, and to provide comprehensive longitudinal neurocognitive, psychiatric, substance use and everyday functioning assessments on the PWH and HIV- comparison participants. Importantly, our core will provide the neuropsychological and psychiatric (including depression) assessments in order to determine neurobehavioral phenotypes. The new NBP Core will apply assessment expertise in conducting comprehensive neuropsychological, psychiatric (including both psychiatric diagnoses and dimensional symptom levels), substance use, and daily functioning assessments. In support of the HNRC’s increased focus on combined neurobehavioral phenotypes among PWH, and participants who change over time, the NBP Core will administer a more detailed psychiatric assessment which will examine detailed components of depression (e.g., anhedonia, apathy), anxiety, stress, adverse childhood events and life trauma, and resilience and social support. All of these factors may influence the complex relationships among neurocognition, depression, HIV disease and other clinical outcomes. The NBP Core and its investigators will continue to serve as national and international leaders in the neuroHIV field, spurring the development of both international harmonization of assessments and new methods, while adapting to the continually evolving scientific landscape.

The NeuroVirology and Biology Core will focus on four major themes underlying NeuroHIV: 1) the impact of viral epigenetics on HIV persistence in the central nervous system (CNS), 2) latent or clinically asymptomatic co-infections, 3) mitochondrial biogenesis, 4) brain macrophage and astroglial response to systemic mediators of inflammation and current antiretroviral therapy (ART). The NVB Core is structured in two complementary units: The NeuroVirology Unit has a research focus on HIV persistence within the CNS and will continue to offer assays to characterize the HIV reservoir in the brain and in myeloid cells, with a new focus on proviral epigenetics. This Unit will characterize viral (genotypic and phenotypic), and other factors (co-infections, inflammation, mitochondrial damage) associated with neurocognitive and other neurobehavioral consequences, such as depression; The NeuroBiology Unit will investigate the effect of ART and HIV on mitochondrial biogenesis in brains, and in vitro in cultures exposed to ART will perform state-of-the-art neurobiology and neuropathology analyses of human brain tissues and in vitro experimental systems, that allow NeuroHIV investigators to understand the cellular mechanisms associated with mood and neurocognitive disorders. It will analyze the potential neurotoxic effects of current ART regimens on specific neuroglial cell populations. In support of the Center’s expanded focus on depression and depression related factors, this unit will study the impact of anti-depressant medication on neuronal homeostasis, focusing on markers of autophagy and associated gatekeepers, e.g., brain immunophilins.

The Microbiome Core plays an essential role in the HNRC by enabling researchers to investigate the emerging, complex links between the gut microbiome, HIV, associated comorbidities, and biological mechanisms involved in neurocognitive impairment (NCI), mood disorders, and more complex neurobehavioral phenotypes that include both. The main goal of MIBI is therefore to make microbiome and metabolome technology broadly available to HNRC investigators, allowing us to go beyond the 16S rRNA profiling from the NeuroGerm (NG) core in the previous funding period, and focusing on microbiome-related mechanisms of mood and cognitive changes in people with HIV (PWH). To provide insight beyond taxonomic profiling, we will use advanced shotgun metagenomics techniques to read out and assemble bacterial and viral genomes from stool and plasma, and relate these to chemical profiles from untargeted metabolomics, which will also capture drugs and their downstream metabolites and allow us to connect these processes to the microbiome in PWH. Additionally, because analysis of highly multivariate microbiome and metabolome data is challenging, an important goal of MIBI will be to provide bioinformatics support and training in how to integrate these data layers with each other and with clinical data important to furthering these scientific aims.

The HNRC Executive Team is charged with guiding the Center’s scientific direction and allocation of resources. In addition to the HNRC Director (R. Heaton), the Executive Team is comprised of the Center Co-Director (I. Grant), Associate HNRC Directors R. Ellis and S. Letendre, and D. Moore, the Center Manager (J. Iudicello) and the Associate Center Manager (D. Franklin). The Executive Team’s work is informed internally by the HNRC Council of Investigators, and externally by the Scientific Advisory Board, Community Advisory Board, and Participant Advisory Board.
The Administrative Core, through its Coordinating Unit, implements the strategic plan and policies of the Executive Team by coordinating activities of all Cores and Units. Other center-wide resources within the Administrative Core include the Data Management and Information Systems Unit, Statistics Unit, and Participant Accrual and Retention Unit. The Core also utilizes several internal committees: a) Research Review Committee (meets weekly to review research proposals, manuscripts and grants, and for scientific updates); b) Human Subjects Committee (participant welfare, assurance of informed consent and confidentiality); and c) HNRC Operations Workgroup (which meets weekly and consist of the Center Manager and the Core Managers and addresses troubleshooting and project implementation across studies.


Despite dramatic reductions in HIV-related mortality and morbidity in the era of modern anti-retroviral therapy (ART), the negative consequences of HIV and related comorbidities on central nervous system (CNS) functioning remains prevalent, with 30-50% of HIV+ patients exhibiting HIV associated neurocognitive disorders (HAND), even in the presence of undetectable viral levels. Although often characterized as mild, such impairments can affect every-day functioning (e.g., the ability to adhere to medication regimens), and their presence may yet yield insights regarding on-going, low-level viral presence in the CNS, and other neuropathological processes. The prevalence of such complications is expected to increase as the HIV-infected population ages. Depression also is highly prevalent among PWH and often can be concurrent with NCI, suggesting that they may share some systemic and neurobiological mechanisms. Like NCI, depression is not a unitary phenomenon: in different patterns and degrees, depressed mood is linked to other mental health factors such as anhedonia, apathy, anxiety, somatic features, and loneliness. The relationships between depression and cognition are complex and remain poorly understood. Depression has been linked to subjective and objective NCI, and with cognitive decline over time. Still, many questions remain regarding the interactions between depression and NCI in PWH, including whether NCI improves following treatment of depression and, if so, which mechanisms underlie such improvements. Thus, the HNRC aims to support mechanistic and clinical studies evaluating the reciprocal effects of cognitive and depressive disorders, and related biological factors (e.g., inflammation, gut dysbiosis) over time.

The overarching aim of the HIV Neurobehavioral Research Center (HNRC) is to provide scientific leadership, research infrastructure, participant resources (cross-sectional and longitudinal data and biospecimens available for associated studies), and technical support for a broad range of research that addresses NIH Office on AIDS Research (OAR) priorities – specifically, comorbidities, coinfections, and complications in persons with HIV (PWH). The HNRC focuses on the mechanisms underlying the development and persistence of central nervous system (CNS) complications in PWH, and factors that may adversely affect PWH. The Center provides resources that facilitate basic, clinical, and translational research that addresses neuroHIV mechanisms and consequences. Areas of ongoing emphasis include HIV eradication from the CNS and alterations in the gut microbiome as contributors to poor CNS outcomes. An area of increased emphasis in this renewal will be depression and how it interacts with cognition to affect outcomes of public health importance, including healthcare engagement, disease progression, everyday functioning, and quality of life. Major thematic areas HNRC activity will support include:

1. Identification of multidimensional neurobehavioral phenotypes relevant to HIV outcomes. Several pathways can converge to present as mood or cognitive disturbances in HIV. Progress in understanding the mechanisms and possibly specific interventions require more precise characterization of these neurobehavioral symptom complexes. For example, in those PWH with evidence of neuroinflammation, is there a distinct cognitive-mood profile (phenotype) that differs from NCI without a mood problem, or vice versa? Depression is not a unitary construct, and may be better understood as multiple components such as depressed mood/sadness, anxiety/fear, anhedonia, apathy, and loneliness. We will use both dimensional and diagnostic assessment approaches to depression, as well as to cognition, to facilitate a nuanced understanding of phenotypes and their underlying biological factors. More precise delineation of neurobehavioral phenotypes should more strongly link to HIV disease and treatment variables (vs. comorbidities), as well as everyday functioning and overall life quality. Examples of key questions include: What neurobehavioral phenotypes are seen in PWH, and how can they be reliably classified in individuals? Are some such phenotypes relatively stable (trait-like), whereas others more likely to change over time? What are their biological bases (e.g., inflammation, gut dysbiosis, metabolic syndrome)? Are changes in neurobehavioral phenotypes over time associated with changes in biological factors, everyday functioning, and/or life quality? What modifies these associations? Can knowledge of neurobehavioral phenotypes support more effective prevention and treatment strategies in PWH?

2. HIV eradication in the CNS. We will continue to support studies on viral persistence, latency, reactivation, and eradication in the CNS. Examples of questions supported by the HNRC infrastructure are: What are the systemic correlates of the brain HIV reservoir, their dynamics, and response to antiretroviral therapy (ART)? How do proviral epigenetics influence HIV persistence in the CNS? How do latent co-infections affect neuroHIV? How does HIV modulate host epigenetics in the brain, and does this affect neurobehavior? What are the mechanisms of HIV- and ART-induced mitochondrial dysfunction and how do they relate to neurobehavioral phenotypes?

3. Influence of the gut microbiome on neuroHIV. We will continue to support investigations into under-explored mechanisms of mood and cognitive disorders in PWH. Examples of relevant questions that supported studies could address include: How does the microbiome affect the CNS and contribute to neurobehavioral phenotypes in PWH? How do these associations change over time? To what extent do they result from microbial metabolites compared with circulating mediators of immune activation? Does gut dysbiosis affect drug metabolism and bioavailability, including ART and antidepressants? Can interventions that alter the gut microbiome improve mood, cognition, and other CNS outcomes?

4. Neurobehavioral relevance of emerging HIV treatments. Examples of treatment-related questions the HNRC resource can facilitate are: What is the influence of emerging therapies, such as long-acting ART drugs and broadly neutralizing antibodies on neurobehavioral outcomes? Are there neurotoxic or neuroprotective effects of new ART and non-ART drugs? What new biomarkers better diagnose or predict mood and cognitive disorders in PWH? How can these and other tools be translated into clinically useful methods?

To support such investigations HNRC will: 1) Maintain a Participant Registry of HIV+ and HIV- participants with longitudinal data; 2) Enhance, maintain, and provide data and biospecimen resources to support new neuroHIV research; 3) Refine novel remote assessment capabilities and onsite assessment methods; 3) Provide expertise, intellectual leadership, and mentoring to support new research and new investigators in neuroHIV; and 4) Provide funding to support pilot studies that will lead to impactful findings and new research project applications and will advance the careers of new investigators.

Lastly, the HNRC will continue its highly successful approach to enhancing infrastructure and capacity-building, both domestically and internationally, as a means of multiplying the value of investments in the HNRC. In particular, we shall continue to serve as an incubator of trainees and young investigators that can populate the next generation of HIV neuroAIDS scientists.

Our Mission

The mission of the HIV Neurobehavioral Research Center (HNRC) is to increase our understanding of how HIV and other diseases affect the human nervous system. The Center is supported by public funding from the National Institutes of Health, the State of California, and other sources. The HNRC conducts local, national, and international research devoted to advancing our knowledge of the prevention, diagnosis and treatment of HIV-related diseases as they affect the brain and nervous system, and result in impairment of everyday functioning.


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