Biology subjects

Tomer, S.

Publications and source records attributed to Tomer, S..

3 recordsLinked to original sources

bioRxiv2025

A Novel Glia-immune humanized mouse model for investigation of HIV CNS infection and neuroinflammation.

Dysregulation in neuroimmune interactions drives pathology in diverse neurological disorders. However, human cell-based in vivo models are limited for clinically relevant mechanistic studies and drug testing. To address this, we developed a novel humanized mouse model integrating all four major types of human glia - astrocytes, oligodendrocyte precursor cells (OPCs), oligodendrocytes, and microglia - in the brain, alongside donor-matched human immune system in peripheral blood and lymphoid tissues. We applied this model to study HIV-associated neurocognitive disorders, which can persist in tissue reservoirs including in the brain despite viral suppression by antiretroviral therapy. These glia-immune humanized mice supported robust HIV-1 replication in the peripheral blood, lymphoid tissues, and the brain, and recapitulated the synapse loss observed in patients. Furthermore, HIV-infected mice exhibited heightened inflammation in both peripheral and brain tissues. Notably, OPCs and oligodendrocytes in HIV-infected brains adopted an immune activated phenotype, upregulating interferon-stimulated genes, highlighting understudied roles of oligodendroglia in HIV infection. RNA-sequencing of human glia identified the upregulation of inflammasome-associated genes and the downregulation of genes involved in transcriptional, epigenetic, and metabolic regulation. Overall, this model provides a powerful in vivo platform to investigate human neuroimmune interactions relevant to diverse neurological disorders, offering critical insights into HIV CNS infection, pathology, and potential therapeutic strategies targeting CNS reservoirs and neuroinflammatory pathways.

immunology↗

bioRxiv2024

Rapamycin Enhances CAR-T Control of HIV Replication and Reservoir Elimination in vivo.

Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a powerful immune therapy for various diseases. Our studies in humanized mice and non-human primates (NHPs) demonstrate that hematopoietic stem cell (HSCs) modified with anti-HIV CAR leads to lifelong engraftment and supply of functional anti-viral CAR-T cells, leading to significantly reduced viral rebound after ART withdrawal. However, T cell exhaustion, driven by chronic immune activation, remains a major challenge for the continuous efficacy of CAR-T therapy, necessitating additional measures to achieve functional cure. We recently showed that in vivo treatment with low dose rapamycin reduced chronic inflammation and improved anti-HIV T cell function in HIV-infected humanized mice. Here, we report that rapamycin significantly improved CAR-T cell function both in vitro and in vivo. In vitro treatment with rapamycin improved CAR-T cell mitochondria respiration and cytotoxicity. In vivo treatment with low-dose rapamycin in HIV-infected, CAR-HSC treated mice reduced chronic inflammation, prevented exhaustion of CAR-T cells and improved CAR-T control of viral replication compared to CAR-HSCs treatment alone. RNAseq analysis of sorted CAR-T cells from humanized mice showed that rapamycin significantly modified the CAR-T cell transcriptome, including the downregulation of multiple check point inhibitors and the upregulation of key genes related to cell survival. We also observed significantly delayed viral rebound after ART withdrawal and diminished HIV reservoir in mice that were treated with rapamycin and CAR-HSCs as compared to CAR-HSCs treatment alone. Taken together, our data indicate that HSCs-based anti-HIV CAR-T combined with rapamycin treatment is a promising approach for treating persistent inflammation and improving immune control of HIV replication.

immunology↗

bioRxiv2023

Structural and Biological Evaluations of a Non-Nucleoside STING Agonist Specific for Human STING-A230 Variants

Previously we identified a non-nucleotide tricyclic agonist BDW568 that activates human STING (stimulator of interferon genes) gene variant containing A230 in a human monocyte cell line (THP-1). STINGA230 alleles, including HAQ and AQ, are less common STING variants in human population. To further characterize the mechanism of BDW568, we obtained the crystal structure of the C-terminal domain of STINGA230 complexed with BDW-OH (active metabolite of BDW568) at 1.95 [A] resolution and found the planar tricyclic structure in BDW-OH dimerizes in the STING binding pocket and mimics the two nucleobases of the endogenous STING ligand 2,3-cGAMP. This binding mode also resembles a known synthetic ligand of human STING, MSA-2, but not another tricyclic mouse STING agonist DMXAA. Structure-activity-relationship (SAR) studies revealed that all three heterocycles in BDW568 and the S-acetate side chain are critical for retaining the compounds activity. BDW568 could robustly activate the STING pathway in human primary peripheral blood mononuclear cells (PBMCs) with STINGA230 genotype from healthy individuals. We also observed BDW568 could robustly activate type I interferon signaling in purified human primary macrophages that were transduced with lentivirus expressing STINGA230, suggesting its potential use to selectively activate genetically engineered macrophages in macrophage-based approaches, such as chimeric antigen receptor (CAR)-macrophage immunotherapies.

pharmacology and toxicology↗