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Principal Investigator: Howard E Gendelman
Organization: UNIVERSITY OF NEBRASKA MEDICAL CENTER
Fiscal Year: 2021
Award: $688,500
Funding agency: National Institute of Neurological Disorders and Stroke
ABSTRACT
Mononuclear phagocytes (MP; monocytes, macrophages, dendritic cells. and microglia) serve as human
immunodeficiency virus type one (HIV-1) reservoirs, sites of viral persistence and latency, and inducers of end-
organ disease. All are commonly linked to HIV-1 pathobiology. However, the key relevance of the MP viral
reservoir rests in the central nervous system (CNS) of those people living with HIV (PLWH). In those PLWH and
receiving antiretroviral therapy (ART), the evidence for the size, scope, and disease relevance of the CNS viral
reservoir remains under appreciated. The discordance between laboratory MP infection and tissue persistence
in an infected human host is also not yet known. MP can have an extended life span and possess self-renewing
potential, and as such, are likely more relevant in disease than currently appreciated. Evaluation of the
significance of MPs, in general, and the microglia specifically will help define the importance of MPs during
natural infection. For the CNS specifically, HIV-1 enters the brain soon after infection and replicates in
perivascular macrophages and MGL along with limited numbers of astrocytes. Viral set point and timing of ART
initiation determines the latent reservoir size; each affects the efficiency of any eradication strategy. Knowledge
of the viral dynamics, CNS viral invasion, susceptibility to MP infection, and composition of CNS HIV reservoir
will facilitate effective therapeutic interventions. To each of these ends, we will employ novel techniques to study
the MP HIV-1 reservoir in laboratory systems and in a newly developed human microglial mouse model of human
disease. We will use basic and applied MP biology, theranostics, novel ART nanoformulations, molecular and
cellular biology, and our unique animal model to study the means to eliminate viral infection at the subcellular,
cellular, and tissue level with newly designed and novel therapeutic methods that include gene therapy
strategies. Our aims are to determine the efficiency of viral suppression by native and nanoformulated ART (at
subcellular level), assess the breadth of the CNS viral reservoirs against viral set points (defined by the initiation
of ART), and to explore combination strategies for HIV-1 elimination in a new developed humanized microglial
mouse.
Terms: <AIDS Virus><Abscission><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adventitial Cell><Affect><Animal Model><Animal Models and Related Studies><Anti-Retroviral Agents><Antiretroviral Agents><Astrocytes><Astrocytus><Astroglia><Autoregulation><BBB function><Biochemical><Biodistribution><Biological><Biology><Birth><Blood monocyte><Body Tissues><Brain><Brain Nervous System><CD34><CD34 gene><CNS Nervous System><CRISPR><CRISPR/Cas system><Cell Body><Cells><Central Nervous System><Clustered Regularly Interspaced Short Palindromic Repeats><Complex><DNA><DNA Therapy><Dendritic Cells><Deoxyribonucleic Acid><Detection><Disease><Disorder><Drugs><Encephalon><Evaluation><Evolution><Excision><Extirpation><Formulation><Foundations><Gene Transfer Clinical><Generalized Growth><Genes><Genetic Intervention><Giant Cells><Goals><Growth><Guide RNA><HIV><HPCA1><HSC transplantation><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><Homeostasis><Hortega cell><Human><Human Immunodeficiency Viruses><Hydrophobicity><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Infection><Interruption><Knowledge><LAV-HTLV-III><Laboratories><Length of Life><Link><Longevity><Lymphadenopathy-Associated Virus><Lymphatic Tissue><Lymphoid><Lymphoid Tissue><Marrow monocyte><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Medication><Medicinal Chemistry><Medulla Spinalis><Methods><Mice><Mice Mammals><Microglia><Mind><Modern Man><Molecular><Molecular and Cellular Biology><Mononuclear><Multinucleated Giant Cells><Murine><Mus><Myelogenous><Myeloid><Mφ><Nebraska><Neuraxis><Non-Polyadenylated RNA><Nuclear><Organ><Parturition><Pathway interactions><Penetration><Pericapillary Cell><Pericytes><Peripheral><Perivascular Cell><Phagocytes><Phagocytic Cell><Pharmaceutic Chemistry><Pharmaceutic Preparations><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacology><Physiological Homeostasis><Polykaryocytes><Polymer Chemistry><Predisposition><Proteins><RNA><RNA Gene Products><Radiolabeled><Recycling><Removal><Reporter><Research><Research Activity><Rest><Ribonucleic Acid><Rouget Cells><Site><Speed><Spinal Cord><Sterilization><Subcellular Fractions><Surgical Removal><Susceptibility><Syncytium><System><Techniques><Testing><Therapeutic><Therapeutic Intervention><Tissue Growth><Tissues><Transmission><Tropism><Tzanck Cell><Variant><Variation><Veiled Cells><Viral><Viral Diseases><Viral reservoir><Virus><Virus Diseases><Virus Replication><Virus reservoir><Virus-HIV><Work><amebocyte><animal imaging><anti-retroviral><anti-retroviral therapy><anti-retroviral treatment><antiretroviral><antiretroviral therapy><antiretroviral treatment><astrocytic glia><base><bio-imaging><bioimaging><biomedical imaging><blood-brain barrier function><bloodbrain barrier function><brain tissue><chronic infection><design><designing><drug/agent><experiment><experimental research><experimental study><fluorophore><gRNA><gene therapeutics><gene therapy><gene-based therapeutic><gene-based therapeutics><gene-based therapy><genes therapeutic><genes therapeutics><genetic therapy><genomic therapy><gitter cell><human disease><human model><humanized mice><humanized mouse><immunoaffinity chromatography><improved><innovate><innovation><innovative><intervention therapy><late endosome><life span><lifespan><lipid nanoparticle><lipophilicity><macrophage><memory CD4 T cell><memory CD4 T lymphocyte><mesoglia><microglial cell><microgliocyte><model of animal><model of human><model organism><monocyte><mouse model><murine model><nano crystal><nano formulation><nano particle><nano-sized particle><nanocrystal><nanoformulation><nanoparticle><nanosized particle><neuro-AIDS><neuro-HIV><neuroAIDS><neuroHIV><neurocognitive disorder><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><ontogeny><particle><pathway><perivascular glial cell><persistent infection><resection><response><self-renew><self-renewal><single-molecule FRET><single-molecule fluorescence resonance energy transfer><site targeted delivery><smFRET><targeted delivery><theranostics><therapeutic evaluation><therapeutic gene><therapeutic testing><therapeutically effective><trafficking><transmission process><viral infection><viral multiplication><viral rebound><viral replication><virology><virus infection><virus multiplication><virus rebound><virus-induced disease>