Examining the effects of the HIV-1 protein Tat and morphine on antiretroviral accumulation and distribution within the brain.

Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, neuro-acquired HIV (neuroHIV) remains a significant problem and approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND). Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, neuronal injury and synaptodendritic culling, viral replication, and potentially altering antiretroviral concentrations within the brain. The present study examined the effects of HIV and morphine co-exposure on the accumulation and spatial distribution of antiretroviral drugs across multiple regions within the brain in an HIV-1 Tat transgenic mouse model by using infrared-matrix-assisted laser desorption electrospray ionization mass spectrometry imaging (IR-MALDESI MSI). Morphine exposure uniquely decreased antiretroviral concentrations in anterior cerebral (primary motor and somatosensory) cortices, corpus collosum (anterior forceps), caudoputamen, nucleus accumbens, and posterior regions including the hippocampus, corpus callosum (main body), cerebral cortex (somatosensory and auditory cortices), thalamus, and hypothalamus. Interestingly, male mice experienced greater morphine-associated decreases in antiretroviral concentrations than females. The study also assessed whether changes in antiretroviral concentrations were linked with inflammation in astroglia, assessed through the measurement of astroglial activation using glial fibrillary acidic protein (GFAP) as a marker. Alterations in antiretroviral concentrations co-registering with areas of astroglial activation exhibited sex-specific treatment differences. This study highlights the intricate interplay between HIV, opioids, and antiretroviral drugs within the CNS, elucidating distinct regional and sex variations in responsiveness. Our findings emphasize the identification of vulnerabilities within the neural landscape and underscore the necessity of carefully monitoring opioid use to maintain the efficacy of antiretroviral therapies.

Fentanyl dysregulates neuroinflammation and disrupts blood-brain barrier integrity in HIV-1 Tat transgenic mice.

Opioid overdose deaths have dramatically increased by 781% from 1999 to 2021. In the setting of HIV, opioid drug abuse exacerbates neurotoxic effects of HIV in the brain, as opioids enhance viral replication, promote neuronal dysfunction and injury, and dysregulate an already compromised inflammatory response. Despite the rise in fentanyl abuse and the close association between opioid abuse and HIV infection, the interactive comorbidity between fentanyl abuse and HIV has yet to be examined in vivo. The HIV-1 Tat-transgenic mouse model was used to understand the interactive effects between fentanyl and HIV. Tat is an essential protein produced during HIV that drives the transcription of new virions and exerts neurotoxic effects within the brain. The Tat-transgenic mouse model uses a glial fibrillary acidic protein (GFAP)-driven tetracycline promoter which limits Tat production to the brain and this model is well used for examining mechanisms related to neuroHIV. After 7 days of fentanyl exposure, brains were harvested. Tight junction proteins, the vascular cell adhesion molecule, and platelet-derived growth factor receptor-ß were measured to examine the integrity of the blood brain barrier. The immune response was assessed using a mouse-specific multiplex chemokine assay. For the first time in vivo, we demonstrate that fentanyl by itself can severely disrupt the blood-brain barrier and dysregulate the immune response. In addition, we reveal associations between inflammatory markers and tight junction proteins at the blood-brain barrier.

Independent actions by HIV-1 Tat and morphine to increase recruitment of monocyte-derived macrophages into the brain in a region-specific manner.

Despite advances in the treatment of human immunodeficiency virus (HIV), approximately one-half of people infected with HIV (PWH) experience neurocognitive impairment. Opioid use disorder (OUD) can exacerbate the cognitive and pathological changes seen in PWH. HIV increases inflammation and immune cell trafficking into the brain; however, less is known about how opioid use disorder affects the recruitment of immune cells. Accordingly, we examined the temporal consequences of HIV-1 Tat and/or morphine on the recruitment of endocytic cells (predominantly perivascular macrophages and microglia) in the dorsal striatum and hippocampus by infusing multi-colored, fluorescently labeled dextrans before and after exposure. To address this question, transgenic mice that conditionally expressed HIV-1 Tat (Tat+), or their control counterparts (Tat-), received three sequential intracerebroventricular (i.c.v.) infusions of Cascade Blue-, Alexa Fluor 488-, and Alexa Fluor 594-labeled dextrans, respectively infused 1 day before, 1-day after, or 13-days after morphine and/or Tat exposure. At the end of the study, the number of cells labeled with each fluorescent dextran were counted. The data demonstrated a significantly higher influx of newly-labeled cells into the perivascular space than into the parenchyma. In the striatum, Tat or morphine exposure increased the number of endocytic cells in the perivascular space, while only morphine increased the recruitment of endocytic cells into the parenchyma. In the hippocampus, morphine (but not Tat) increased the influx of dextran-labeled cells into the perivascular space, but there were too few labeled cells within the hippocampal parenchyma to analyze. Collectively, these data suggest that HIV-1 Tat and morphine act independently to increase the recruitment of endocytic cells into the brain in a region-specific manner.