Mechanisms of HIV-1-induced inflammation during active replication in human microglia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE318503 | GEO | 2026/09/02
REPOSITORIES: GEO
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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:Although antiretroviral therapy (ART) effectively suppresses HIV-1 replication to undetectable levels and restores many immune parameters in people living with HIV (PLWH), these individuals remain at elevated risk for HIV-associated comorbidities. Among the most prevalent is neurocognitive impairment—a mild form of HIV-associated neurocognitive disorders (HAND)—which affects up to 50% of PLWH. Despite extensive investigation, the precise mechanisms underlying HAND pathogenesis remain unclear, in part due to its multifactorial nature. To address this, we conducted a comparative single-nucleus multi-omics analysis—integrating RNA sequencing (RNA-seq) and chromatin accessibility profiling (ATAC-seq)—of post-mortem brain tissues from HIV-infected individuals with and without HAND, as well as uninfected controls. Our results reveal substantial dysregulation in genes involved in inflammation, innate immunity, glycosylation, and cholesterol metabolism in HIV-infected brains (HAND+ and HAND−) relative to uninfected controls. Notably, these changes were further accentuated in HAND+ samples compared to HAND−, with microglia and oligodendrocytes emerging as the most affected cell populations—highlighting their potential central role in sustaining neuroinflammation. Interestingly, we observed a disconnect between transcriptomic and epigenomic signals: many inflammation-related genes located in accessible chromatin regions in HAND+ brains were not transcriptionally upregulated. This epigenetic priming—particularly in microglia and astrocytes—is consistent with the concept of trained immunity (TRIM), wherein prior exposures epigenetically “train” innate immune cells to respond differently to subsequent stimuli. Our findings suggest that maladaptive TRIM may be a key contributor to persistent neuroinflammation and the pathogenesis of HAND in the ART era.
2025-05-16 | GSE296943 | GEO
Project description:Antiretroviral therapy (ART) has the potency of suppressing systemic viral replication and spread. Still, persistent human immunodeficiency virus type-1 (HIV) survive for decades during treatment in latently infected cells, making up the latent viral reservoir. This reservoir is believed to reside in subtypes of memory T cells and cell from monocytic lineages, but some functional and naïve T cells have also shown to carry latent HIV. Eradication of latently infected cells, in terms of a sterilizing cure, have proven to be a hurdle since there is a heterogeneity in mechanisms governing latency and integration site into the genome. Over the course of suppressive therapy, persisting HIV, sustained by low levels of viral replication, homeostatic proliferation, and cell to cell transmission, is a driver of chronic immune activation in the body. For the immune system to elicit an appropriate inflammatory response it is dependent on secretion of inflammatory molecules, such as chemokines and cytokines. Most chemokines are pro-inflammatory factors that facilitate leukocyte recruitment to site of inflammation where they can exert their regulatory role in response to pathological and physiological stressors e.g., infection, inflammation, and tissue damage. Alterations in chemokine receptor expression and chemokine levels modulates the activity of the immune response and in HIV infection contribute to chronic inflammation and mortality. Therefore, people living with HIV on suppressive therapy (PLWH) are at higher risk of age associated co-morbidities due to elevated immune activation and chronic inflammation induced by ART toxicities, microbiome dysbiosis leading to microbial translocation and dysregulated immune cell activation and function. As a result, the causative HIV pathogenesis and immune dysfunction further chronic immune activation. This result in a vicious cycle as immune activation is driver of HIV disease progression and inflammaeging leading to earlier onset of age-related diseases. An alternative approach in cure strategies is a functional cure for HIV aiming at suppressing viral replication without ART. A model for functional cure studies are elite controllers (EC). EC constitute a small fraction of HIV+ individuals (<0.5%) exhibiting the unique characteristic of natural control of viral replication in absence of ART. However, there is a population-based heterogeneity of how these individuals naturally supress viral replication. This heterogeneity is caused by viral genetic factors, variability of integration site in the human genome, together with host response against the pathogen and immunological factors. In terms of immune cell activation, studies have shown how EC maintain lower levels of inflammatory markers compared to PLWH. Contradictory, some studies have shown elevated inflammatory markers in EC which could be attributed to the heterogeneity of the EC group or as others have shown it is a consequence of loss of spontaneous control of HIV. Therefore, as no consensus exist further studies comparing variability of immune function between EC and ART can aid in understanding the mechanisms of natural control of HIV. In our recent study (Sperk et al 2021, iScience) we hypothesised that modulated CCR6/CCL20 chemokine axis and CCR2-CCL7-CCL2 signalling can play a protective role in the EC phenotype. Downregulation of CCR2 and CCR6 receptors in lymphocytes and higher plasma abundance of CCL4, CCL7 and CCL20 in EC compared to the HIV-negative controls can provide natural resistance to HIV-infection. In the present study, we further extended our analysis to evaluate the expression profile dynamics of key chemokine receptors, CCR2, CCR3, CCR5 and CCR6, in successfully treated PLWH. We compared well treated PLWH with HIV-1 elite controllers and its association with HIV-1 persistence. Furthermore, cell populations of interest were isolated for liquid chromatography mass spectrometry (LC-MS/MS) based untargeted proteomics analysis to evaluate specific characteristics regulating these cell populations and their role in HIV persistence. Our study provides important understanding of the chemokine receptor dynamics and its role in HIV persistence that differentiate elite controllers from long term treated PLWH.
2022-04-22 | PXD027749 | Pride
Project description:The crosstalk between intestinal epithelial cells (IEC) and Th17-polarized CD4+ T-cells is critical for mucosal homeostasis, with HIV-1 causing major alterations in people living with HIV (PLWH) despite antiretroviral therapy (ART). Here, we used a model of IEC:T-cell co-culture to investigate the effects of IL-17A and TNF, two cytokines produced by Th17-cells, in regulating IEC ability to promote de novo infection and viral outgrowth from reservoir cells. Our results demonstrated that IL-17A in the presence/absence of TNF acts on IEC to increase HIV capture and trans infection of CD3/CD28-activated T-cells from uninfected individuals. Also, IL-17A-exposed IEC significantly increased HIV replication and outgrowth in CD3/CD28-activated T-cells infected with HIV in vitro and isolated from ART-treated PLWH, respectively. Exposure of IEC to IL-17A resulted in decreased type I IFN levels, as measured using the 293T-KEK cell based assay. Illumina RNA sequencing performed on cytokine-activated IEC before/after co-culture with T-cells of ART-treated PLWH revealed a molecular signature associated with IL-17A-mediated proviral effects. This signature includes decreased expression of transcripts linked to type I IFN production/response (DDX60, IRF7, STAT1) and HIV restriction (IFITM1, TRIM5, IF2AK2, MX1, MX2, IFIT1,3,5, PARP12, HERC6, ISG15, viperin, BST2, OAS2/3), and increased expression of Th17-attracting chemokines (CCL20).
2021-03-01 | GSE147045 | GEO
Project description:Knowledge on immune activation in the brain during acute HIV infection is crucial for the prevention and treatment of HIV associated neurological disorders (HAND), which is prevalent in people living with HIV (PLWH), even in those treated with antiretroviral therapy. In this study, we determined regional brain (basal ganglia, thalamus, and frontal cortex) immune and virological profiles 7 and 14 days after infection (dpi) with SIVmac239 in rhesus macaques. Basal ganglia and thalamus were infected earlier (7dpi) than frontal cortex (14 dpi) and contained higher quantities of viruses than the latter. Increased immune activation of astrocytes and significant infiltration of monocytes/macrophages in thalamus at 14 dpi coincided with elevated plasma viral load, while SIV was only localized within monocytes/macrophages. RNA signatures of pro-inflammatory responses including IL-6 were detected at 7 dpi in microglia and interestingly preceded reliable detection of virus in tissues and was maintained long term in the brain of chronically infected macaques. Countering the pro-inflammatory response, the anti-inflammatory response was detectable, but delayed till 14 dpi, as TGF-β expression in significantly higher numbers of perivascular monocytes/macrophages; though this anti-inflammatory response was not detected in chronic infection. Our data provide evidence that the interplay of acute pro-inflammatory and anti-inflammatory responses in the brain likely contribute to the overt neuro-inflammation, but that inflammatory markers such as IL-6 may serve as hyperacute biomarkers of low-level brain infection.
2024-08-17 | GSE182427 | GEO
Project description:Treatment with latency-reversing agents (LRAs) alone has been ineffective in reducing HIV-1 reservoirs in people living with HIV-1 (PLWH) who are on antiretroviral therapy (ART), due to inefficiencies in reservoir reactivation and adaptive immune responses. However, NK cells activated with cytokines may be able to target HIV-1 reservoirs more effectively. To explore the therapeutic potential of NK cells, we expanded blood NK cells from multiple donors ex vivo into CD56brightCD16+ “eNK” cells using artificial antigen-presenting cells (aAPCs) expressing membrane-bound IL21. eNK cells express multiple activating receptors and are highly cytotoxic against specific target cells. They can also kill HIV-infected CD4+ T cells via antibody-dependent cell-mediated cytotoxicity (ADCC) using broadly neutralizing antibodies (bNAbs) against HIV-1 Env gp120/gp41. Notably, eNK cells from PLWH on ART efficiently killed autologous HIV-1+ T cells reactivated by a combination of vorinostat (SAHA) and IL-15 or an IL-15 superagonist (N-803), as evidenced by declines in proviral load, inducible HIV-1 mRNA, and virus release. Adoptive immunotherapy with eNK cells combined with LRA treatment thus presents a promising strategy to reduce the latent HIV-1 reservoir in PLWH.
2025-12-29 | GSE312273 | GEO
Project description:HIV Associated Neurocognitive Disorder (HAND) is a condition behaviorally characterized by cognitive and neurological impairments, and pathologically characterized by neuroinflammation and a loss of synaptic integrity and function. Although therapeutics exist to increase the lifespan of people living with HIV, they are not effective at preventing HIV induced neuronal damage and the prevalence of HAND remains virtually unchanged. We observed an increase in expression of ephrin-B/EphB in post-mortem CNS specimen of people who lived with HIV and brain pathology. Given the previously recognized impact of EphB2 on inflammation in the periphery, the functional role of EphB2-mediated ephrin-B reverse signaling on microglia was assessed. A a pro-inflammatory and antiviral mRNA expression profile was observed. The stimulation produced condirioned media, including secreted inflammatory factors, that were sufficient to induce non-cell contact-dependent neurotoxicity. Finally, knockdown of microglial ephrin-B1, EphB2 binding partner, resulted in a partial alleviation of the microglial pro-inflammatory signature and subsequent neurotoxicity. In this study, we show that elevated EphB2, and its reverse signaling through ephrin-B1 in microglia, can drive neuroinflammation and toxicity suggesting this pathway can mediate neurotoxicity in neuroHIV. Furthermore, we propose that this neuroinflammatory mechanism may play a role in promoting other neurodegenerative diseases.
2024-06-01 | GSE260757 | GEO
Project description:Understanding why PLWH remain highly susceptible to TB despite anti-retroviral therapy (ART) is critical for improving treatment and prevention strategies. We aimed to determine how HIV impacts the transcriptional responses of AMs and other immune cells in response to Mtb infection at the single cell level using ScRNAseq. Our analyses revealed that transcriptional responses of AMs from PLWH following Mtb infection show significant deficits in costimulatory capacity and TNF/IL-6 signaling networks.
2025-01-28 | GSE266696 | GEO
Project description:HIV-associated neurocognitive disorders (HAND) persist as a notable cause of illness among individuals with HIV. Despite significant progress in antiretroviral therapy (ART), HAND continues to be a major concern, impacting approximately one-third of those infected with HIV. Recent research underscores the pivotal role of microglia, the primary immune cells in the central nervous system (CNS), in the development and progression of HAND. The infection and activation of microglia by HIV leads to the release of pro-inflammatory markers, cytokines, chemokines, secondary messengers, and reactive oxygen species (ROS). These factors collectively initiate signalling pathways that contribute to neuroinflammation, a central process in the development of HAND. In order to validate stem cell-derived microglia (iMGL) as a viable model system for HAND investigation, we infected iMGLs and human monocyte-derived macrophages (MDMs) with the primary HIV-1 isolate Ba-L at an MOI of 0.25. Total RNA was extracted from cell populations on days 1, 2, 4, 6, and 8 following infection. Subsequently, we conducted bulk RNA sequencing to examine the longitudinal transcriptomic alterations induced by the virus over this time frame
2024-05-01 | GSE248998 | GEO
Project description:HIV-associated neurocognitive disorders (HAND) persist as a notable cause of illness among individuals with HIV. Despite significant progress in antiretroviral therapy (ART), HAND continues to be a major concern, impacting approximately one-third of those infected with HIV. Recent research underscores the pivotal role of microglia, the primary immune cells in the central nervous system (CNS), in the development and progression of HAND. The infection and activation of microglia by HIV leads to the release of pro-inflammatory markers, cytokines, chemokines, secondary messengers, and reactive oxygen species (ROS). These factors collectively initiate signalling pathways that contribute to neuroinflammation, a central process in the development of HAND. In order to validate stem cell-derived microglia (iMGL) as a viable model system for HAND investigation, we infected iMGLs and human monocyte-derived macrophages (MDMs) with the primary HIV-1 isolate Ba-L at an MOI of 0.25. Total RNA was extracted from cell populations on days 1, 2, 4, 6, and 8 following infection. Subsequently, we conducted bulk RNA sequencing to examine the longitudinal transcriptomic alterations induced by the virus over this time frame
2024-05-01 | GSE248997 | GEO