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Project description:HIV associated neurocognitive impairment (HIV-NCI), a comorbidity of HIV infection, affects up to 50% of people with HIV (PWH). HIV-infected monocytes that transmigrate across the blood brain barrier and differentiate into macrophages establish a CNS viral reservoir that activates and infects parenchymal cells, contributing to neuronal damage that characterizes HIV-NCI. Methamphetamine (meth) use is prevalent in PWH and further impairs cognitive functioning. To examine whether meth-mediated dysregulation of macrophage functions may contribute to increased HIV-NCI, we characterized differential gene expression in primary human HIV-infected macrophages treated daily with meth for five days by RNA-sequencing. We identified increases in multiple gene isoforms of metallothionein 1 (MT1), a heavy metal binding protein involved in protective mechanisms against metal toxicity and oxidative stress. Nuclear localization of MT1 protein was previously shown to either positively or negatively affect NF-κB activity in a cell type specific manner, with nuclear MT1 contributing to LPS-induced TNF-α and IL-6 in macrophages. We found that daily meth treatment for one to five days increased nuclear localization of MT1 in macrophages acutely infected with HIV which was associated with increased LPS-induced CXCL8 and CCL8, and a trend towards increased basal and/or LPS-induced expression of other cytokines/chemokines, including TNF-α and IL-6, that was donor specific. ROS levels were not changed with meth treatment although there was a donor specific trend towards increased ROS with multiple days of meth treatment. These data indicate that repeated exposure of macrophages to meth in the context of HIV increases nuclear MT1 localization, which is associated with increased inflammatory mediator production, and therefore may be a mechanism that contributes to meth-mediated exacerbation of HIV-NCI.
2025-09-29 | GSE307858 | GEO
Project description:HIV associated neurocognitive impairment (HIV-NCI), a comorbidity of HIV infection, affects up to 50% of people with HIV (PWH). HIV-infected monocytes that transmigrate across the blood brain barrier and differentiate into macrophages establish a CNS viral reservoir that activates and infects parenchymal cells, contributing to neuronal damage that characterizes HIV-NCI. Methamphetamine (meth) use is prevalent in PWH and further impairs cognitive functioning. To examine whether meth-mediated dysregulation of macrophage functions may contribute to increased HIV-NCI, we characterized differential gene expression in primary human HIV-infected macrophages treated daily with meth for five days by RNA-sequencing. We identified increases in multiple gene isoforms of metallothionein 1 (MT1), a heavy metal binding protein involved in protective mechanisms against metal toxicity and oxidative stress. Nuclear localization of MT1 protein was previously shown to either positively or negatively affect NF-κB activity in a cell type specific manner, with nuclear MT1 contributing to LPS-induced TNF-α and IL-6 in macrophages. We found that daily meth treatment for one to five days increased nuclear localization of MT1 in macrophages acutely infected with HIV which was associated with increased LPS-induced CXCL8 and CCL8, and a trend towards increased basal and/or LPS-induced expression of other cytokines/chemokines, including TNF-α and IL-6, that was donor specific. ROS levels were not changed with meth treatment although there was a donor specific trend towards increased ROS with multiple days of meth treatment. These data indicate that repeated exposure of macrophages to meth in the context of HIV increases nuclear MT1 localization, which is associated with increased inflammatory mediator production, and therefore may be a mechanism that contributes to meth-mediated exacerbation of HIV-NCI.
2025-09-29 | GSE307856 | GEO
Project description:Methamphetamine Induces Metallothionein 1 Expression and an Inflammatory Phenotype in Primary Human HIV-infected Macrophages
| PRJNA1327422 | ENA
Project description:Methamphetamine Induces Metallothionein 1 Expression and an Inflammatory Phenotype in Primary Human HIV-infected Macrophages [JW98_JW100]
| PRJNA1327425 | ENA
Project description:Methamphetamine Induces Metallothionein 1 Expression and an Inflammatory Phenotype in Primary Human HIV-infected Macrophages [JW81_JW82_JW84]
| PRJNA1327426 | ENA
Project description:Macrophages are important effector cells of the immune system and play an important role in mounting inflammatory responses. Macrophages can be activated by different stimuli in the tissue, either by cytokines produced by T helper cells (M1 or M2 polarization) or by the pathogens they encounter. Macrophages are also important target cells of HIV-1 and are preferentially infected by CCR5-using viruses. In this study, we investigated the ability of HIV-1 to induce changes in gene expression in unpolarized macrophages as well as in M1 or M2 polarized cells. We observed that CCR5-using HIV-1 regulates the expression of genes that are also regulated by IL-4 in macrophages. Genes regulated by HIV-1 infection and IL-4 polarization are involved in dampening pro-inflammatory responses in macrophages, which may facilitate HIV-1 to escape from detection by other immune cells. We also observed that changes in macrophage gene expression triggered by CCR5-using HIV-1 differed from those regulated by a CXCR4-using virus. This indicates that CCR5-using HIV-1 may be able to modulate macrophage gene expression to achieve successful replication. Our results provide insight in the complex interplay between HIV-1 and cells of the immune system. Polarized macrophages were obtained by stimulation of primary human monocytes with IFN-gamma (250 U/ml) in combination with TNF-alpha (12.5 ng/ml) (M1), IL-4 (50 ng/ml) (M2a), IL-10 (50 ng/ml) (M2c) for 5 days. Cells were inoculated for 24 hours with one of two HIV-1 strains (CCR5 or CXCR4 using HIV1) or their non replicating counterparts (heat inactivated virus). Macrophages that were not stimulated wiht cyokines or inoculates with HIV-1 were used as control. A total of 16 treatment conditions were tested in triplicate, for a total of 48 samples analysed.
2015-08-01 | E-GEOD-55029 | biostudies-arrayexpress
Project description:HIV-associated neurocognitive impairment (HIV-NCI) persists in 15-40% of people with HIV (PWH) despite effective antiretroviral therapy. HIV-NCI significantly impacts quality of life, and there is currently no effective treatment for it. The development of HIV-NCI is complex and is mediated, in part, by the entry of HIV-infected mature monocytes into the central nervous system (CNS). Once in the CNS, these cells release inflammatory mediators that lead to neuroinflammation, and subsequent neuronal damage. Infected monocytes may infect other CNS cells as well as differentiate into macrophages, thus contributing to viral reservoirs and chronic neuroinflammation. Substance use disorders in PWH, including the use of methamphetamine (meth), can exacerbate HIV neuropathogenesis. We characterized the effects of meth on the transcriptional profile of HIV-infected mature monocytes using RNA-sequencing. We found that meth mediated an upregulation of gene transcripts related to viral infection, cell adhesion, cytoskeletal arrangement, and extracellular matrix remodeling. We also identified downregulation of several gene transcripts involved in pathogen recognition, antigen presentation, and oxidative phosphorylation pathways. These transcriptomic changes suggest that meth increases the infiltration of mature monocytes that have a migratory phenotype into the CNS, contributing to dysregulated inflammatory responses and viral reservoir establishment and persistence, both of which contribute to neuronal damage. Overall, our results highlight potential molecules that may be targeted for therapy to limit the effects of meth on HIV neuropathogenesis.
| S-EPMC9433802 | biostudies-literature
Project description:Macrophages play a critical role in inflammation and antigen-presentation. Abnormal macrophage function has been attributed in autoimmune diseases and cancer progression. Recent evidence suggests that high salt tissue micro-environment causes changes in macrophage activation. In our current report, we studied the role of extracellular sodium chloride on phenotype changes in peripheral circulating monocyte/macrophages collected from healthy donors. High salt (0.2 M NaCl vs basal 0.1 M NaCl) treatment resulted in a decrease in MΦ1 macrophage phenotype (CD11b+CD14highCD16low) from 77.4±6.2% (0.1 M) to 29.3±5.7% (0.2 M, p<0.05), while there was an increase in MΦ2 macrophage phenotype (CD11b+ CD14lowCD16high) from 17.2±5.9% (0.1 M) to 67.4±9.4% (0.2 M, p<0.05). ELISA-based cytokine analysis demonstrated that high salt treatment induced decreased expression of in the MΦ1 phenotype specific pro-inflammatory cytokine, TNFα (3.3 fold), IL-12 (2.3 fold), CCL-10 (2 fold) and CCL-5 (3.8 fold), but conversely induced an enhanced expression MΦ2-like phenotype specific anti-inflammatory cytokine, IL-10, TGFβ, CCL-17 (3.7 fold) and CCR-2 (4.3 fold). Further high salt treatment significantly decreased phagocytic efficiency of macrophages and inducible nitric oxide synthetase expression. Taken together, these data suggest that high salt extracellular environment induces an anti-inflammatory MΦ2-like macrophage phenotype with poor phagocytic and potentially reduced antigen presentation capacity commonly found in tumor microenvironment.
| S-EPMC4877052 | biostudies-literature
Project description:Human monocyte-derived macrophages (hMDM) were differentiated in the presence and absence of methamphetamine. Post differentiation, hMDMs were infected with human immunodeficiency virus (HIVADA). To investigate the effects of Meth exposure on infected macrophages day 5 post HIVADA infection, RNA was isolated from HIVADA hMDMs and sequenced using Next Generation Sequencing performed on the Illumina NextSeq550.
2021-09-28 | GSE160323 | GEO
Project description:Macrophages are important effector cells of the immune system and play an important role in mounting inflammatory responses. Macrophages can be activated by different stimuli in the tissue, either by cytokines produced by T helper cells (M1 or M2 polarization) or by the pathogens they encounter. Macrophages are also important target cells of HIV-1 and are preferentially infected by CCR5-using viruses. In this study, we investigated the ability of HIV-1 to induce changes in gene expression in unpolarized macrophages as well as in M1 or M2 polarized cells. We observed that CCR5-using HIV-1 regulates the expression of genes that are also regulated by IL-4 in macrophages. Genes regulated by HIV-1 infection and IL-4 polarization are involved in dampening pro-inflammatory responses in macrophages, which may facilitate HIV-1 to escape from detection by other immune cells. We also observed that changes in macrophage gene expression triggered by CCR5-using HIV-1 differed from those regulated by a CXCR4-using virus. This indicates that CCR5-using HIV-1 may be able to modulate macrophage gene expression to achieve successful replication. Our results provide insight in the complex interplay between HIV-1 and cells of the immune system.
2015-08-01 | GSE55029 | GEO