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α4 Blockade Reduces CD8 TEM Cells in the Brain and Elevates CNS Viral Loads

ABSTRACT: Background. The blood-brain barrier (BBB) regulates immune cell entry into the CNS, and various strategies have been developed to target this barrier in efforts to alleviate neuroinflammation in neurodegenerative diseases. α4β1 is crucial for T cell influx into the CNS. In the context of HIV, CD4 T cells drive viral infiltration, while CD8 T cells are essential for viral clearance. This dual role complicates strategies aimed at targeting T cell entry during HIV infection, yet it remains an area that has not been thoroughly explored. Methods. We investigated the impact of disrupting α4-mediated T cell entry into the CNS in SIVmac251-infected rhesus macaques treated with an α4-blocking antibody (n=4) versus an isotype control (n=4). Our comprehensive approach included single-cell analysis of CD45+ cells in the brain and spleen, spatial transcriptomics of the hippocampus, viral load measurements, and flow cytometry on brain tissue. Results. Single-cell analysis revealed a marked reduction in the brain CD8 TEM cluster, particularly in cells expressing Granulysin, CCL5, and STAT4, while CD4 T cell clusters remained unchanged, and two monocyte clusters were enriched. This shift was accompanied by an increase in brain SIV RNA+ CD45+ CD4+ T cells in the α4-treated group (vRNA+ cells = 60) compared to controls (n=11). Spatial transcriptomics of SIV vRNA+ versus SIV vRNA- regions in the hippocampus of α4-treated macaques showed enrichment of CD4 TCM and monocyte gene signatures. Correspondingly, quantitative PCR revealed higher vRNA levels in the gray matter of the PFC, STS, and Hp. These findings suggest that α4 blockade selectively disrupts CD8 TEM populations while sparing CD4 T cells, leading to elevated viral loads and heightened neuroinflammation. The increase in SIV RNA+ CD4+ T cells and viral loads in the gray matter furthermore underscores the compartmentalized effect of α4-mediated immune modulation on viral dynamics across distinct brain regions Conclusion. These results underscore the critical need to evaluate immune-targeting therapies, with implications for strategies aimed at controlling T cell influx in the context of viral infections in the brain.

ORGANISM(S): blank sample Macaca mulatta

PROVIDER: GSE279903 | GEO | 2024/11/01

REPOSITORIES: GEO

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Project description:Although HIV-1 can directly infect resting CD4+ T cells, virus replication in resting CD4+T cells is very inefficient owing to the different host restriction factors blocking viral replication. The accessory protein Vpx from the major simian immunodeficiency virus (SIV) of rhesus macaque (mac) and HIV-2 lineage could degrade a host restriction factor, SAM and HD domain containing protein 1 (SAMHD1), to facilitate HIV reverse transcription. Interestingly, Vpx proteins from a second SIV lineage, the SIV of redcapped mangabeys or mandrills (SIVrcm/nmd-2), had no effect on SAMHD1 and did not affect the dNTP pool, but strongly increased HIV-1 infection in resting CD4+ T cells although not in primary macrophages. This indicates that Vpx, in addition to SAMHD1,can overcome a previously unexplored restriction factor for lentiviruses. Here to identify this potential restriction factor, we examined Vpxrcm-interacting cellular proteins and found that keratin 72 (KRT72), an intermediate filament protein that is exclusively expressed in resting CD4+ T cells, is a new host antiviral factor targeted by Vpx. Other than Vpx from SIV mac and HIV-2, the Vpxrcm/nmd-2 lineage, which had no effect on the SAMHD1 protein, could strongly promote the degradation of KRT72, resulting in enhanced HIV-1 infection in resting CD4+ T cells. Furthermore, we discovered that KRT72 restricts HIV-1 replication by sequestering incoming HIV-1 capsids in cytoplasmic intermediate filaments (IFs). In the presence of KRT72, HIV-1 capsid cores become attached to the IF and their trafficking toward the nucleus is inhibited. In contrast, in the absence of KRT72, HIV-1 capsids are transported into the nucleus,leading to high levels of integrated HIV-1 DNA. In addition, KRT72 expression was substantially higher in resting CD4+ T cells than in activated CD4+ T cells, and it was rapidly reduced by T cell activation. Collectively, the results show that KRT72 is a new Vpx-counteracted host antiviral factor that acts to tether incoming capsids to the cytoplasmic IF, thereby restricting HIV-1 infection in resting CD4+ T cells.