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Principal Investigator: Michal Toborek
Organization: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $471,362
Funding agency: National Institute of Mental Health
ABSTRACT
HIV-1-infected individuals are at a higher risk for non-AIDS related co-morbidities, including cerebrovascular
and neurological diseases. These pathologies may be driven, at least in part, by low levels of viral replication
that persist in HIV-infected brains, which can lead to immune activation, chronic inflammation, and viral
reactivation. Experiments on microglia, astrocytes, and brain pericytes indicate that these cells are all capable,
to different degrees, to harbor HIV infection. We have pioneered research on HIV-1 infection in brain pericytes,
and indicated that these cells possess the receptor profile enabling HIV-1 infection. Recent evidence on
pericyte ontogeny identified that a substantial subpopulation of brain pericytes originates from myeloid
progenitors. We recently demonstrated HIV-1-infected pericytes in human brains with HIV encephalitis.
Furthermore, our new and exciting preliminary data suggest that brain pericytes may be capable of latent
infection and reactivation, similar to other myeloid cells. Based on these observations, we hypothesize that
brain pericytes are a key, albeit previously unrecognized, cell type for the formation of HIV-1
reservoirs in the CNS. The overarching goal of the current proposal is to characterize the latent HIV-
1 infection in brain pericytes as the necessary step for successful eradication of CNS reservoirs and
HIV cure. Consistent with this goal, Specific Aims will evaluate the formation of latent HIV infection in brain
pericytes both in vivo and in vitro. In a cohort of human brain samples with a history of achieved viral
suppression obtained from the National NeuroAIDS Tissue Consortium (NNTC), we will determine whether
brain pericytes harbor latent HIV-1 infections in HIV-suppressed patients (Aim 1). In addition, we will evaluate
transcriptional signatures of latently HIV-1-infected human primary brain pericytes (Aim 2), and delineate
functional outcomes associated with HIV infection of brain pericytes (Aim 3).
The focus on the role of pericytes in the development of viral brain HIV reservoirs is an innovative and cutting-
edge conceptual approach, consistent with the current RFA. Focusing on pericytes as a novel myeloid cell
population in the context of HIV-1 infection and brain reservoirs has also a paradigm-changing potential and
is likely to lead to new discoveries in the field. The planned experiments will help us to better characterize the
pericyte reservoirs in the CNS in order to design future therapies for reservoir clearance and HIV cure.
Terms: <AIDS Virus><AIDS/HIV><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Address><Adventitial Cell><Astrocytes><Astrocytus><Astroglia><Attention><Autoregulation><Biology><Blood - brain barrier anatomy><Blood monocyte><Blood-Brain Barrier><Brain><Brain Nervous System><Brain Vascular><Brain Vascular Disorders><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cerebral vascular pericyte><Cerebrovascular Disease><Cerebrovascular Disorders><Chronic><Communicating Junction><Coupling><DNA><Data><Dendritic Cells><Deoxyribonucleic Acid><Development><Dysfunction><Encephalon><Endothelial Cells><Expression Signature><Functional disorder><Future><Gap Junctions><Gene Expression Profile><Generalized Growth><Goals><Growth><HIV><HIV Infections><HIV associated neurological disease><HIV associated neurological disorder><HIV encephalitis><HIV-1><HIV-I><HIV/AIDS><HIV1><HTLV-III Infections><HTLV-III-LAV Infections><Hemato-Encephalic Barrier><History><Homeostasis><Hortega cell><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Immune Cell Activation><Immune system><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Impairment><In Situ Hybridization><In Vitro><Individual><Infection><Inflammation><Intracellular Communication and Signaling><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Knowledge><LAV-HTLV-III><Latent virus infection phase><Life Cycle><Life Cycle Stages><Low-resistance Junction><Lymphadenopathy-Associated Virus><Macrophage><Marrow monocyte><Metabolic><Methods><Microglia><Modern Man><Myelogenous><Myeloid><Myeloid Cells><Myeloid Progenitor><Myeloid Progenitor Cells><Myeloid Stem Cells><Mφ><NNTC><Names><National NeuroAids Tissue Consortium><Nervous System Diseases><Nervous System Disorder><Neurocognitive><Neurologic><Neurologic Disorders><Neurological><Neurological Disorders><Nexus Junction><Non-Polyadenylated RNA><Pathogenesis><Pathology><Patients><Pericapillary Cell><Pericytes><Perivascular Cell><Physiological Homeostasis><Physiopathology><Population><Predisposition><Productivity><Proviruses><Publishing><RNA><RNA Gene Products><Receptor Protein><Recording of previous events><Reporter><Research><Ribonucleic Acid><Role><Rouget Cells><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Sorting><Susceptibility><Tissue Growth><Transmission><Veiled Cells><Viral><Viral reservoir><Virus><Virus Replication><Virus reservoir><Virus-HIV><Work><astrocytic glia><biological signal transduction><bloodbrain barrier><brain pericytes><brain perivascular cell><brain vascular disease><brain vascular dysfunction><brain vascular pericyte><cell type><cerebral pericyte><cerebral vascular><cerebral vascular disease><cerebral vascular dysfunction><cerebro-vascular><cerebrovascular><cerebrovascular dysfunction><cerebrovascular pericyte><co-morbid><co-morbidity><cohort><comorbidity><design><designing><developmental><experiment><experimental research><experimental study><experiments><functional outcomes><gene expression pattern><gene expression signature><gitter cell><global gene expression><global transcription profile><high risk><histories><human immunodeficiency virus encephalitis><immune activation><in situ Hybridization Genetics><in situ Hybridization Staining Method><in situ imaging><in vivo><innovate><innovation><innovative><intracranial vascular dysfunction><latent infection><latent viral infection><latent virus infection><life course><mesoglia><microglial cell><microgliocyte><monocyte><myeloid stem and progenitor cell><name><named><naming><neuro-AIDS><neuro-HIV><neuro-vascular><neuro-vascular unit><neuroAIDS><neuroHIV><neurological disease><neuropathologic><neuropathological><neuropathology><neurovascular><neurovascular unit><novel><ontogeny><pathophysiology><perivascular glial cell><pharmacologic><receptor><sensor><social role><transcriptional profile><transcriptional signature><transcriptome><transmission process><viral multiplication><viral replication><virus multiplication>