Cannabinoid Receptor 2 Agonists Attenuate HIV Replication and Inflammatory Activation in HIV-infected Myeloid Cells
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PROVIDER: PRJNA1054626 | ENA |
REPOSITORIES: ENA
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Project description:Emerging evidence suggests brain-resident myeloid cells, including macrophages and microglia, provide a reservoir for HIV infection in the central nervous system (CNS), and their inflammatory activation is a proposed pathogenic mechanism in HIV-associated neurocognitive disorders (HAND). We investigated whether cannabinoid receptor 2 (CB2), an immunomodulatory receptor expressed in myeloid cells, regulates viral replication and inflammation in HIV-infected macrophages and microglia. Using the synthetic CB2-specific agonist, JWH-133, we found that CB2 activation reduces HIV replication in primary human monocyte-derived macrophages (MDMs) and human iPSC-derived microglia (iMg) at differing doses, corresponding to the basal expression of CNR2 and related endocannabinoid transcripts in each cell type. Direct CB2 agonism via JWH-133 broadly reduced cytokine release from HIV-infected MDMs, but not iMg. RNA-seq revealed that CB2 agonism primarily altered interferon and integrated stress response pathways in MDMs; homeostatic pathways, including synapse maintenance and phagocytosis, were altered in iMg. Further investigation in iMg found NLRP3 inflammasome activation, but not priming, was reduced by CB2 activation. This study identifies key discrepancies in CB2 response between myeloid cell types and implicates CB2-specific agonists as promising candidates for regulation of HIV-associated neuroinflammation.
2025-01-22 | GSE250616 | GEO
Project description:The endocannabinoid system (ECS) provides regulatory functions in several cellular and physiological processes. It has also been found to play a role in control of cancer development. Our group found that breast cancer cells responded to cannabinoid receptor (CB) agonist treatments. This leads the activation of CB receptors in breast cancer, which inhibited their growth. In addition, breast cancer cells also behaved differentially when they were exposed to combinations of both CB1 and CB2 agonists. The underlying mechanism of individual- or co- activation after CB agonist exposure is still unknown. Hence, we studied the impact of CB activation on cancer molecular signature by performing proteomic analysis after triple-negative breast cancer (MDA-MB-231) cells exposed to CB receptor agonists. In this study, ACEA and GW405833 were used as CB1 and CB2 receptor agonists, respectively.
2024-07-27 | PXD040666 | Pride
Project description:To investigate the mechanisms of chronic psychological stress-induced cardiac injury and the protective mechanisms of cannabinoid type II agonists in a model of psychological stress-induced cardiac injury We constructed a mouse chronic psychological stress model based on a chronic unpredictable stress pattern. Mice were randomly divided into control, case (psychological stress group), and treatment groups (post-stress with the cannabinoid type II receptor agonist JWH133) to begin a 3-week psychological stress procedure, and cardiac tissue was subsequently removed for whole-transcriptome sequencing
2022-12-30 | GSE210820 | GEO
Project description:Retroviral integration is mediated by a unique enzymatic process shared by all retroviruses and retrotransposons. During integration, double-stranded linear viral DNA is inserted into the host genome in a process catalyzed by viral-encoded integrase. However, host cell defenses against HIV-1 integration are not clear. This study identifies -catenin-like protein 1 (CTNNBL1) as a potent inhibitor of HIV-1 integration via association with viral IN and its cofactor, lens epithelium-derived growth factor/p75. CTNNBL1 overexpression blocks HIV-1 integration and inhibits viral replication, whereas CTNNBL1 depletion significantly upregulates HIV-1 integration into the genome of various target cells. Further, CTNNBL1 expression is downregulated in CD4+ T cells by activation, and CTNNBL1 depletion also facilitates HIV-1 integration in resting CD4+ T cells. Thus, host cells may employ CTNNBL1 to inhibit HIV-1 integration into the genome. This finding suggests a strategy for the treatment of HIV infections.
2022-02-24 | PXD031853 |
Project description:Host protein folding stress responses can play important roles in RNA virus replication and evolution. Intriguingly, prior work revealed a complicated interplay between the cytosolic proteostasis stress response, controlled by its master regulator heat shock factor 1 (HSF1) and human immunodeficiency virus-1 (HIV-1). We sought to isolate HSF1 transcription factor activity from proteostasis stress and elucidate the function of HSF1 in HIV-1 lifecycle in absence of cellular stress. We used chemical genetic, stress-independent control of HSF1 activity to establish whether and how HSF1 influences HIV-1 replication. Stress-independent HSF1 induction decreased both the total quantity and infectivity of HIV-1 virions. Moreover, HIV-1 was unable to escape HSF1-mediated restriction over the course of several serial passages. These results promote continued consideration of the heat shock response as a potential target for antiviral drugs.
2022-01-30 | GSE137591 | GEO
Project description:HSF1 Activation Can Restrict HIV Replication
| PRJNA565977 | ENA
Project description:Infiltrating monocytes and macrophages play a crucial role in the progression of HIV-1 infection in the CNS. Previous studies showed that activation of the CB? can attenuate inflammatory responses and affect HIV-1 infectivity in T cells and microglia. Here, we report that CB? agonists can also act as immunomodulators on HIV-1-infected macrophages. First, our findings indicated the presence of elevated levels of CB? expression on monocytes/macrophages in perivascular cuffs of postmortem HIV-1 encephalitic cases. In vitro analysis by FACS of primary human monocytes revealed a step-wise increase in CB? surface expression in monocytes, MDMs, and HIV-1-infected MDMs. We next tested the notion that up-regulation of CB? may allow for the use of synthetic CB? agonist to limit HIV-1 infection. Two commercially available CB? agonists, JWH133 and GP1a, and a resorcinol-based CB? agonist, O-1966, were evaluated. Results from measurements of HIV-1 RT activity in the culture media of 7 day-infected cells showed a significant decrease in RT activity when the CB? agonist was present. Furthermore, CB? activation also partially inhibited the expression of HIV-1 pol. CB? agonists did not modulate surface expression of CXCR4 or CCR5 detected by FACS. We speculate that these findings indicate that prevention of viral entry is not a central mechanism for CB?-mediated suppression in viral replication. However, CB? may affect the HIV-1 replication machinery. Results from a single-round infection with the pseudotyped virus revealed a marked decrease in HIV-1 LTR activation by the CB? ligands. Together, these results indicate that CB? may offer a means to limit HIV-1 infection in macrophages.
| S-EPMC3629438 | biostudies-literature
Project description:Type I interferon plays a critical role in the control of viral infections, including HIV-1. Interferon induces a number of restriction factors that block HIV-1 entry, replication and release from the host cell. Currently, systemic treatment of HIV-1 infection with interferon has little efficacy in the clinic due to side effects including fatigue and flu-like symptoms. However, understanding the role of interferon in HIV-1 restriction, and developing molecular tools to generate type I interferons locally, provide an opportunity to inhibit HIV-1 replication while avoiding the side effects associated with systemic administration. Here, we tested a constitutively active inducer of high levels of interferon beta (dLMP1-MAVS). Supernatant from cell transfected with dLMP1-MAVS inhibited HIV-1 replication in both culture cells and primary human CD4+ T cells. CD4+ T cells upregulated a number of known HIV-1 restriction factors, including Viperin, Tetherin, MxB, and ISG56 in response to dLMP1-MAVS. In addition, dLMP1-MAVS activated human dendritic and acted as a molecular adjuvant in a mouse HIV-1 vaccine model. Our study generates new insights into the role of type I interferon in HIV-1 restriction, and provides a novel strategy to induce both type I interferon and anti-HIV-1 immune responses at sites of ongoing viral replication.
2015-06-01 | GSE65541 | GEO
Project description:We evaluated cutaneous contact hypersensitivity (CHS) in Cnr1-/-/Cnr2-/- animals using the obligate contact allergen 2,4-dinitrofluorobenzene (DNFB), which generates a specific cutaneous T-cell mediated allergic response upon repeated allergen contact. Allergic contact dermatitis affects about 5% of men and 11% of women in industrialized countries and is one of the leading causes for occupational diseases. In an animal model for cutaneous contact hypersensitivity we show that mice lacking both known cannabinoid receptors display exacerbated allergic inflammation. In contrast, fatty acid amide hydrolase deficient mice, which have increased levels of the endocannabinoid anandamide, displayed reduced allergic responses in the skin. Cannabinoid receptor antagonists exacerbated whereas receptor agonists attenuated allergic inflammation. These results demonstrate a protective role of the endocannabinoid system in contact allergy in the skin, and suggest a novel target for therapeutic intervention. Keywords: Strain (Wt versus Ko) and disease state (DNFB treated versus control).
2007-06-11 | GSE7694 | GEO
Project description:Studying the effects of HIV infection on the host transcriptome has typically focused on protein-coding genes. However, recent advances in the field of RNA sequencing revealed that long non-coding RNAs (lncRNAs) add an extensive additional layer to the cell’s molecular network and are highly involved in the regulation of molecular processes, including gene expression. Here, we performed transcriptome profiling throughout a primary HIV infection in vitro to investigate lncRNA expression at the different HIV replication cycle processes (reverse transcription, integration and particle production). Subsequently, guilt-by-association, transcription factor and co-expression analysis were performed to infer biological roles for the lncRNAs identified in the HIV-host interplay. Many lncRNAs were shown to play a role in mechanisms relying on proteasomal and ubiquitinylation pathways, apoptosis, DNA damage responses and cell cycle regulation. Through transcription factor binding analysis, we found that lncRNAs display a distinct transcriptional regulation profile as compared to protein coding mRNAs, suggesting that mRNAs and lncRNAs are independently modulated from each other. In addition, we identified five differentially expressed lncRNA-mRNA pairs with mRNA involvement in HIV pathogenesis (HIV linked co-expression) with possible cis regulatory lncRNAs that control the nearby mRNA expression and function. Altogether, the present study demonstrates that lncRNAs add a new dimension to the HIV-host interplay and should be further investigated as they may represent targets for controlling HIV replication.
2016-10-31 | GSE74818 | GEO