About the HNRC

Welcome to the HIV Neurobehavioral Research Center

University of California, Department of Psychiatry

The HNRC has established itself as a productive, multidisciplinary endeavor whose organization, resources, and procedures have fostered multi-investigator and multidisciplinary cooperative research.

Research Areas

The HNRC is organized as a set of Scientific Cores and a Developmental Core, with the work of these entities being harmonized by a Coordinating Core. The Scientific Cores were chosen to provide the techniques and resources necessary for the next generation of neuroAIDS research. They include Cores in NeuroAssessment, NeuroGerm, and Neurobiology.

The NeuroAssessment Core proposes a focus on a) collecting and processing stool for microbiome assays; b) characterizing processes that accelerate premature aging; and c) including measuring frailty, metabolic syndrome, vascular pathology, and biomarkers identified in HNRC studies and the ARC Biomarker project as predictive of HAND.  These include multiple viral, inflammatory and neuronal biomarkers. Also neurobehavioral assessments in the U.S. and in international collaborative projects will benefit from continued, active development and updating of demographically corrected normative standards for neurocognitive tests (and norms for detecting significant change over time) based upon accumulation of new data in HNRC and affiliated projects; as well as from supported research assessments of declines in everyday functioning.  Finally, improved or updated multimodal neuroimaging methods will be adopted.

The NeuroGerm Core proposes a variety of innovative assays for: a) determining clonal expansion of HIV-infected cells, b) measuring replication competent provirus levels, c) detecting very low levels of viral concentration in fluids and tissues, d) measuring HIV DNA and both cell-free and cell-associated HIV RNA, e) detecting and quantifying mitochondrial damage, f) determining methylation patterns in blood and the CNS, g) characterizing the gut microbiome (metabolomics profiling as well as 16S), and h) assessing biomarkers for microbial translocation and inflammation.

The Neurobiology Core proposes to offer novel immunocytochemical, biochemical and molecular studies related to HIV persistence and eradication (chromatin modifiers), epigenetic markers that regulate gene expression, expression of microRNAs, markers of viral production and cycling, and cyclin-dependent replication kinases;  to the microbiome theme (patterns of neuro-inflammation, neuro-vascular unit injury, and gut pathology); to the HIV and aging theme (novel markers of mitochondrial biogenesis and mitophagy, autophagy, proteinopathies); as well as expanded marking of neurodegeneration (including studies of selective neuronal populations and neurogenesis). Please see NeuroAssessment Core, NeuroGerm Core and Neurobiology Core proposals for detailed descriptions of these and other methodological advances planned for the renewal period.

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), Core Directors R. Ellis and S. Letendre, and Center Manager and Neurobehavioral Unit Head (T. Marcotte). 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); 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; and d) Thematic Interest Groups organized around Center themes.  These interest groups include those that focus on the cure agenda, microbiome studies, and studies of aging.

SPECIFIC AIMS

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 everyday 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.

The overarching aim of the renewal of the HIV Neurobehavioral Research Center (HNRC) is to provide the intellectual/scientific expertise, research infrastructure, and cohorts (longitudinal, as well as a participant registry) to serve as a catalyst for studies addressing key NIH Office on AIDS Research (OAR) priorities in the field of neuroAIDS. In particular, we will be addressing:

1) Eradication and “cure” within the CNS. Addressing the OAR priority of “Innovative multidisciplinary research and international collaborations to develop novel approaches and strategies to eliminate viral reservoirs that could lead toward a cure or lifelong remission of HIV infection, including studies on viral persistence, latency, reactivation, and eradication”, a focus during this renewal will be to address questions such as: How do we define CNS cure and is it different from a systemic cure? What is the size of HIV DNA populations in the brain and where are they distributed? How much HIV DNA remains in patients with virologic suppression on ART? Can HIV DNA in the brain be reached using “kick and kill” interventions? Will this be safe? Are HIV DNA populations in brain replication competent? What is the impact of early, clinical, immunologic, and virologic events, do they set a course for future neurologic conditions, and what can these early events tell us regarding mechanisms for development of HAND? Can early ART initiation and behavioral adherence interventions minimize the size of the brain HIV DNA reservoir?

2) Alterations in the gut microbiota as a contributor to neurocognitive impairment. A second focus is on novel, under-explored pathways/mechanisms for the development and persistence of HAND. We will address the potential role for HIV-related changes in the gut microbiota and how they may influence the development of HAND. This component will address issues such as: Are there systemic events (e.g., microbiome changes) that affect the CNS and contribute to the persistence of HAND in well-treated patients? Is the gut microbiome associated with CNS outcomes over time - neurocognitive performance, imaging findings, and CSF or blood biomarkers? Are these relationships primarily the result of the direct (e.g., vagal signaling from gut to brain) or indirect (e.g., circulating mediators such as products of microbial translocation and metabolites produced by gut bacteria) effects of the gut microbiota? Do microbiome changes with HIV and its treatment affect important comorbid conditions such as obesity and metabolic parameters contributing to chronic inflammation? Can interventions that alter the gut microbiome improve CNS outcomes?

This renewal also includes on-going, continuity areas of emphasis, examining a) mechanisms of aging and HIV interaction on neuroAIDS), addressing the OAR priority to investigate “premature aging associated with long-term HIV disease and ART”, and b) clinical relevance: new treatments/biomarkers/new methods (e.g., Do new ARV and non-ARV treatments alter the development of HAND? What additional biomarkers can be identified/developed to better detect and predict HAND? How can these and other tools be translated into methods that are useful in the clinic?). In addition to the above areas of emphasis, the HNRC will continue to support studies addressing the longstanding themes of the Center - the virus, host, host-virus determinants of HAND, and mechanisms by which these generate neural injury and HAND; the role of co-pathogens and comorbidities; approaches to optimizing treatments to prevent or ameliorate neuro-HIV; and the effects of HAND on everyday functioning, and treatments for restoring productivity.

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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