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Restoring a homeostatic microglia state by combination antiretroviral therapy in SIV-infected rhesus macaques

ABSTRACT: Although modern therapies like cART have transformed HIV from a lethal disease to a manageable condition, associated neurocognitive consequences remain a concern. Paradoxically, microglia and macrophages, which comprise the innate defense system in the brain and are crucial for CNS homeostasis, are targets for HIV and key players in its neuropathogenesis. In addition, these infected cells can serve as viral reservoirs even in effectively treated infection. Here using an scRNA-seq approach in the SIV-NHP model, we demonstrate differential transcriptional programs in brain myeloid cells from monkeys under four conditions: uninfected, chronically SIV-infected, chronically SIV-infected treated with combination antiretroviral therapy (cART), and SIVE. Our study reveals alterations in composition (both lineage and gene expression profiles) of the cell populations between groups. Importantly, treatment with cART largely restored the homeostatic microglia profile present in uninfected animals that was disrupted in SIV-infected untreated animals

ORGANISM(S): Macaca mulatta

PROVIDER: GSE195574 | GEO | 2022/06/22

REPOSITORIES: GEO

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Project description:Human immunodeficiency virus (HIV) is widely recognized for its striking impact on the immune system, and it also significantly impacts the central nervous system (CNS). The primary immune constituents in the brain, microglia and macrophages, are the target for HIV in people and the simian immunodeficiency virus (SIV) in nonhuman primates. This infection can lead to neurological dysfunction, known as HIV-associated neurocognitive disorder (HAND) and pathological entities such as HIV-induced encephalitis (HIVE). Given the gaps in our knowledge on how these cells respond in vivo to CNS infection, we performed single-cell multiomic sequencing, including gene expression and ATAC-seq on myeloid cells from the brains of two rhesus macaques with SIV-induced encephalitis (SIVE) as well as two uninfected controls. We used both RNA expression and chromatin accessibility to identify cell clusters. We found that the myeloid cell populations were significantly changed by SIVE, which differed greatly from those found in the uninfected brains. We categorized myeloid cells in the SIVE brains into two primary phenotypes: microglia-like and CAM-like, which were different from each other regarding trancriptomic profile and chromatin accessibility. We found that these microglia-like cells express high levels of chemoattractants for capable of recruiting highly the activated CAM-like cells to the site of infection/inflammation. Additionally, we observed a dramatic shift of upstream gene regulators and their targets in brain myeloid cells during SIVE. The transcription factors (TFs) highly enriched in SIVE-specific cell clusters were related to IRF/STAT and NF-κB mediated interferon and other proinflammatory cytokines production. Interestingly, some of these TF binding sites were also enriched in the open chromatin identified in the SIV DNA provirus in infected myeloid cells, indicating the immune activation in the host cells might also promote HIV/SIV gene expression and regulation . In summary, this study further uncover the trancriptome, gene regulaory events and potenital roles of differenet brain myeloid phenotypes in SIVE.

Project description:MicroRNAs (miRNAs) have important roles in regulating a plethora of physiological and pathophysiogical processes including neurodegeneration. In both human immunodeficiency virus (HIV)-associated dementia in humans and its monkey model simian immunodeficiency virus encephalitis (SIVE), we find miR-21, a miRNA largely known for its link to oncogenesis, to be significantly upregulated in the brain. In situ hybridization of the diseased brain sections revealed induction of miR-21 in neurons. miR-21 can be induced in neurons by prolonged N-methyl-D-aspartic acid receptor stimulation, an excitotoxic process active in HIV and other neurodegenerative diseases. Introduction of miR-21 into human neurons leads to pathological functional defects. Furthermore, we show that miR-21 specifically targets the mRNA of myocyte enhancer factor 2C (MEF2C), a transcription factor crucial for neuronal function, and reduces its expression. MEF2C is dramatically downregulated in neurons of HIV-associated dementia patients, as well as monkeys with SIVE. Together, this study elucidates a novel role for miR-21 in the brain, not only as a potential signature of neurological disease, but also as a crucial effector of HIV-induced neuronal dysfunction and neurodegeneration. Total cellular RNA was isolated from frozen (−80°C) brain specimens by using TRIzol (Invitrogen, Carlsbad, CA, USA) for the monkey samples, and RNAzol (Biotecx Laboratories, Houston, TX, USA) for the human samples, followed by column purification (miRNeasy, Qiagen, Valencia, CA, USA) as per manufacture's instructions. For the monkeys, four samples were from uninfected animals and four from SIV-infected animals that developed simian AIDS with SIV encephalitis. For the human samples, six samples were from individuals who were HIV negative with no history of dementia or neurocognitive disability and showed no significant neuropathology. Five samples were from HIV positive individuals that were neurocognitively impaired (NNTC clinical rating >6)38 and a neuropathological diagnosis of HIV encephalitis. Clinical information is provided in the supplemental material. For microarray analysis, only three of the HAD specimens were sufficient for use, but all five were used for the qRT-PCR studies.

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Restoring a homeostatic microglia state by combination antiretroviral therapy in SIV-infected rhesus macaques

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