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Single-cell transcriptional analysis of CD45+ cells in the rhesus brain during acute SIV infection.

ABSTRACT: People living with HIV are particularly vulnerable to developing a spectrum of neurocognitive abnormalities referred to as HIV-associated neurocognitive disorders. These disorders have been linked to neurological impairment driven by inflammation within areas of the brain controlling cognition. Current data suggest that HIV establishment within the central nervous system (CNS) occurs within the first weeks following infection and drives subsequent neuroinflammatory processes. Various studies have implicated HIV-target cells (i.e., monocytes, macrophages, and CD4 T cells) as key facilitators of HIV CNS establishment via a “trojan horse” mechanism, in which infected cells cross CNS barrier tissues and contribute to viral seeding. Cellular entry is mediated by integrins, specifically α4 integrins, which are expressed at the blood brain barrier and blood cerebrospinal fluid barrier and allow circulating immune cells to enter the CNS. To investigate the contribution of CNS infiltrating cells to early neurological disease, we utilized an acute rhesus macaque SIVmac251 infection model, where animals were treated with an anti-a4 integrin monoclonal antibody to inhibit immune cell trafficking to the CNS. To gain insights into neuro inflammatory transcriptional programs induced following SIV infection and how this might be modulated by a4 integrin blockade, we utilized single cell (sc) RNA sequencing of FACS sorted CD45+ cells isolated from brain and spleen.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE221815 | GEO | 2023/08/26

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.

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Single-cell transcriptional analysis of CD45+ cells in the rhesus brain during acute SIV infection.

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