Browsing by Subject "HIV Infections"
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Item Blood-Based Inflammation Biomarkers of Neurocognitive Impairment in People Living with HIV(2020-05) Swanta, Naomi K.; Borgmann, Kathleen; Berg, Rance E.; Cunningham, Rebecca L.; Johnson, Leigh A.; Yan, Liang-JunRace and sex minorities are disproportionately affected by HIV in the United States. Approximately 50% of people living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HAND). ART has decreased incidence of HAD but the less severe forms of HAND has increased. Diagnosis of HAND is challenging as the often-subtle forms of impairment are not as overt as dementia. HIV infection promotes neurocognitive dysfunction through persistent inflammation, which correlates with the severity of impairment. The objective of this study was to identify blood-based cytokines that associate with, and could predict, neurocognitive functioning in a demographically balanced cohort of PLWH. Inflammatory biomarkers of HIV-associated neurocognitive impairment could improve current diagnosis methods and may be specific for populations disproportionately affected by the HIV. Seven neurocognitive domains were evaluated in 121 seropositive African American, Non-Hispanic White and White Hispanic men and women using computerized assessments. A panel of 26 inflammation-associated cytokines were measured in plasma and blood mononuclear cells. Significant associations among neurocognitive functioning and HIV-related parameters, relevant sociodemographic variables and cytokine panel were determined using multivariate and univariate regression analyses. Following corrections for education, CD4 T cell counts, viral load and eliminating outliers. Our results demonstrate that chemokine C-C motif ligand (CCL) 8 significantly correlated with memory, complex attention, cognitive flexibility, psychomotor speed, executive functioning and processing speed. Tissue inhibitor of metalloproteinases-1 (TIMP-1) significantly correlated with the aforementioned domains except memory and processing speed. In addition, interleukin (IL) - 23 significantly associated with executive functioning and processing speed. The biomarkers demonstrated a negative correlation to neurocognitive functioning. Race disparities were identified in memory and CCL8, furthermore, sex disparities were identified in executive functioning and TIMP-1. The plasma biomarkers were evaluated as predictive classifiers of neurocognitive functioning. Decision tree models for NCI and executive functioning predicted visit two at 67.2% accuracy. Collectively, these data identified blood-based inflammatory biomarkers of neurocognitive function with the potential to assist in the diagnosis of HIV-associated neurocognitive impairments in PLWH.Item The ER-mitochondrial Interface in astrocytes during methamphetamine exposure and HIV-1 infection(2022-12) Proulx, Jessica M.; Borgmann, Kathleen; Park, InWoo; Cunningham, Rebecca L.; Krishnamoorthy, Raghu R.; Yang, Shaohua; Maddux, Scott D.Early during infection, human immunodeficiency virus 1 (HIV-1) invades the central nervous system (CNS) and can persist for life, despite effective antiretroviral treatment. Infection and activation of residential glial cells leads to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Notably, substance use, including methamphetamine (METH) is disproportionately elevated among people living with HIV-1 and can increase the risk and severity of HAND. Thus, the National Institutes on Drug Abuse have declared HIV-1 and substance use comorbidity as a high research priority. Astrocytes are the most numerous glial cells and provide essential support to neurons. Chronic activation of astrocytes, such as during HAND or METH use disorders, can shift astrocytes to become neurotoxic. Delineating cellular targets to regulate astrocyte function is essential to ensure neuronal fitness during a pathological challenge. Endoplasmic reticulum (ER) and mitochondria contact sites, termed mitochondria-associated ER membranes (MAMs), are key cellular platforms in neuropathology, where calcium dysregulation, unfolded protein response (UPR) sensors, and mitochondrial dysfunction are notable MAM-mediated mechanisms underlying astrocyte dysfunction. We hypothesize that the ER-mitochondria interface may serve as a therapeutic target for astrocyte dysfunction via calcium and non-canonical UPR signaling during HIV-1 and METH pathogenesis. Primary human astrocytes were infected with a pseudotyped HIV-1 and/or exposed to low doses of METH for seven days. Following HIV-1 infection and/or chronic METH exposure, astrocytes had increased mitochondrial respiration, cytosolic calcium flux and protein expression of UPR/MAM mediators. Notably, inositol-requiring enzyme 1α (IRE1α) was prominently upregulated following both HIV-1 infection and chronic METH exposure. Further investigations revealed IRE1α modulates astrocyte mitochondrial respiration, glycolytic function, morphological activation, inflammation, and glutamate uptake. We then investigated a novel METH-binding receptor, trace amine-associated receptor 1 (TAAR1) as a potential upstream regulator to METHinduced UPR/MAM mediator expression. Indeed, selective antagonism of TAAR1 significantly suppressed UPR/MAM protein expression, including IRE1α. Altogether, our findings emphasize the importance and potential therapeutic intervention of UPR/MAM messengers, namely IRE1α and calcium, to combat astrocyte dysfunction, Moreover, TAAR1 may be an upstream target for METH-mediated astrocyte dysfunction.