Document text
Principal Investigator: Oliver I Fregoso
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $607,081
Funding agency: National Institute on Drug Abuse
PROJECT SUMMARY
Approximately 40 million people are currently infected by HIV, with an additional 1.7 million people newly
infected each year. While only a single person has been functionally cured of HIV, advances in antiretroviral
therapy (ART) have drastically decreased AIDS-related illnesses and deaths for individuals on ART. However,
HIV+ patients on ART still face debilitating AIDS-independent diseases, including HIV-associated
neurocognitive disorders (HAND). HAND refers to a spectrum of three neurocognitive disorders that influence
survival, quality of life, and everyday function: asymptomatic neurocognitive impairment (ANI), mild
neurocognitive disorder (MND), and HIV-associated dementia (HAD). While the number of patients with the
more severe forms of HAND have declined since the introduction of ART, an estimated 15-55% of HIV+
patients taking ART still develop a neurocognitive disorder. Patients with ANI are two to six times more likely to
progress to a more severe form of HAND when compared to HIV+ patients who are neurocognitively normal.
Thus, HAND remains an important and prevalent HIV-associated disease to affect individuals in the ART era.
It is now thought that HAND develops because of functional changes in neurons caused by chronic
inflammation and HIV infection of an immune cell in the brain, microglia. Though they are not a neuronal cell,
microglia do play an important role in the general health and function of neural tissue. The immune responses
of microglia are thought to be tightly regulated and controlled as to not normally harm the surrounding neurons.
We do know that HIV can infect microglia. However, little is known about the progression of acute and chronic
HIV infection in microglia nor how and what impact these infected cells have on surrounding neuronal tissue.
Moreover, HIV infection is frequently associated with intravenous drug us such as heroin along with the
growing abuse of prescription opioids. It remains unclear how the use of these drugs alters both neuronal and
innate immune signaling and further contributes to HAND.
One major roadblock in understanding infection of microglia has been the lack of systems for analysis in
culture, as well as means for studying their impact on human brain functions. Recent developments in human
pluripotent stem cell (hPSC)-derived microglia and 3D-brain organoids have opened new doors to understand
HIV infection in these otherwise intractable cells. We have begun to bridge this knowledge gap by leveraging
our strengths in HIV and brain organoid biology to model HAND in culture, where we can finally begin to
answer important questions in the roles of HIV, opioids, and microglia and other cells in this debilitating HIV-
associated disease. Success of our proposed research will 1) define the response of microglia to HIV infection
and opioid treatment, 2) characterize how dysregulated microglia affect brain organoid structure, neural
network health, and signaling, and 3) establish a foundation for therapeutic discovery to reduce
neuroinflammation and HAND.
Terms: <3-D><3-Dimensional><3D><AIDS><AIDS Virus><AIDS dementia><AIDS with dementia><AIDS-related dementia><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immune Deficiency Syndrome related dementia><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acute><Affect><Assay><Astrocytes><Astrocytus><Astroglia><Autopsy><Bioassay><Biological Assay><Biology><Blood monocyte><Body Tissues><Brain><Brain Nervous System><Cell Body><Cell Communication and Signaling><Cell Culture System><Cell Signaling><Cells><Cessation of life><Chronic><Connectionist Models><Consequences of HIV><Death><Dementia Due to HIV Disease><Dementia associated with AIDS><Dementia in human immunodeficiency virus (HIV) disease><Development><Diacetylmorphine><Diamorphine><Dimensions><Disease><Disorder><Drug usage><Drugs><Encephalon><Epidemic><Face><Foundations><Functional Imaging><Gene Expression><Gene Transcription><Genetic Transcription><HIV><HIV 1 associated neurocognitive disorder><HIV Dementia><HIV Infections><HIV associated dementia><HIV associated neurocognitive deficit><HIV associated neurocognitive impairment><HIV induced neurocognitive deficit><HIV induced neurocognitive impairment><HIV neurocognitive impairment><HIV-1><HIV-1 associated dementia><HIV-1 associated neurocognitive deficit><HIV-1 associated neurocognitive disorder><HIV-1 associated neurocognitive impairment><HIV-1 dementia><HIV-I><HIV-associated neurocognitive disorder><HIV-related dementia><HIV1><HTLV-III Infections><HTLV-III-LAV Infections><Health><Heroin><Histopathology><Hortega cell><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><IQ Deficit><Immune><Immune Cell Activation><Immune response><Immune signaling><Immunes><Immunological response><Individual><Infection><Inflammation><Innate Immune Response><Intracellular Communication and Signaling><Intravenous><Knowledge><LAV-HTLV-III><Lymphadenopathy-Associated Virus><Maritally Unattached><Marrow monocyte><Measures><Medication><Microglia><Modeling><Modern Man><Molecular><Monitor><Myeloid Cells><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Network Models><Neural Network Simulation><Neurocognitive><Neurocognitive Deficit><Neurocognitive Impairment in HIV><Neurocognitive Impairment in HIV-1><Neurocyte><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Neurons><Neurophysiology - biologic function><Neuroprotectants><Neuroprotective Agents><Neuroprotective Drugs><Opiates><Opioid><Organoids><Pathology><Patients><Perceptrons><Persons><Pharmaceutical Preparations><Physiologic Imaging><Play><Population><Preclinical Testing><Productivity><QOL><Quality of life><RNA Expression><Research><Role><Signal Transduction><Signal Transduction Systems><Signaling><Single Person><Single-Nucleus Sequencing><Structure><Synapses><Synaptic><System><Systems Analyses><Systems Analysis><Testing><Therapeutic><Tissues><Transcription><Translating><Unmarried person><Viral Burden><Viral Load><Viral Load result><Virus-HIV><acute infection><antiretroviral therapy><antiretroviral treatment><astrocytic glia><biological signal transduction><chronic infection><cytokine><developmental><drug use><drug/agent><experience><faces><facial><gitter cell><host response><human pluripotent stem cell><human progenitor><human stem cells><human tissue><immune activation><immune system response><immunoresponse><in vitro Model><innovate><innovation><innovative><insight><intelligence quotient deficit><mesoglia><method development><microglial cell><microgliocyte><monocyte><necropsy><neural><neural degeneration><neural function><neural inflammation><neural network><neurocognitive decline><neurocognitive disorder><neurocognitive impairment><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neurological disease><neuronal><neuronal degeneration><neuropathologic><neuropathological><neuropathology><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><opioid medication abuse><opioid prescription drug abuse><perivascular glial cell><persistent infection><physiological imaging><postmortem><pre-clinical testing><prescription opiate abuse><prescription opioid abuse><response><sNuc-Seq><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><stem cell technology><success><synapse><three dimensional>