Biology subjects

Peterson, J. J.

Publications and source records attributed to Peterson, J. J..

4 recordsLinked to original sources

bioRxiv2024

Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders

Enzymopathy disorders are the result of missing or defective enzymes. Amongst these enzymopathies, mucopolysaccharidosis type I, is a rare genetic lysosomal storage disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), ultimately causes toxic build-up of glycosaminoglycans (GAGs). There is currently no cure and standard treatments provide insufficient relief to the skeletal structure and central nervous system (CNS). Human memory T cells (Tm) migrate throughout the bodys tissues and can persist for years, making them an attractive approach for cellular-based, systemic enzyme replacement therapy. Here, we tested genetically engineered, IDUA-expressing Tm as a cellular therapy in an immunodeficient mouse model of MPS I. Our results demonstrate that a single dose of engineered Tm leads to detectable IDUA enzyme levels in the blood for up to 22 weeks and reduced urinary GAG excretion. Furthermore, engineered Tm take up residence in nearly all tested tissues, producing IDUA and leading to metabolic correction of GAG levels in the heart, lung, liver, spleen, kidney, bone marrow, and the CNS. Our study indicates that genetically engineered Tm holds great promise as a platform for cellular-based enzyme replacement therapy for the treatment of mucopolysaccharidosis type I and potentially many other enzymopathies and protein deficiencies.

bioengineering↗

bioRxiv2023

The histone methyltransferase SETD2 regulates HIV expression and latency through a post-transcriptional mechanism.

HIV can enter a state of transcriptional latency in CD4 T cells, allowing the virus to evade the host immune system and persist during antiretroviral therapy. Thus, understanding the mechanisms that drive HIV latency, and developing strategies to reactivate viral expression in latently infected cells, are key goals for achieving a cure for HIV. The full spectrum of mechanisms behind the regulation of HIV expression and latency are unclear but include covalent modifications to cellular histones that are associated with the integrated provirus. Here we investigate the role of the SETD2 histone methyltransferase, which deposits H3K36 trimethylation (H3K36me3) cotranscriptionally at genes, in HIV infection. We show that prevention of H3K36me3 through addition of a potent and selective inhibitor of SETD2 (EPZ-719) in human T cells leads to reduced post-integration viral gene expression and accelerated the emergence of a latently infected pool within a population of infected cells. CRISPR/Cas9-mediated knockout of SETD2 in HIV infected primary CD4 T cells confirmed the role of SETD2 in HIV expression. Intriguingly, EPZ-719 exposure also enhanced responsiveness of latently infected cells to latency reversal with the HDAC inhibitor vorinostat. Transcriptomic profiling of EPZ-719 exposed HIV-infected cells identified numerous cellular pathways impacted by EPZ-719. Finally, we show SETD2 inhibition does not affect HIV viral transcription, but instead leads to a shift in the pattern of viral RNA splicing - a result that would be predicted to reduce HIV expression. These results identify SETD2 and H3K36me3 as novel regulators of HIV expression and latency through a post-transcriptional mechanism.

microbiology↗

bioRxiv2022

Integrated single-cell multiomic analysis of HIV latency reversal reveals novel regulators of viral reactivation.

Despite the success of antiretroviral therapy, HIV cannot be cured because of a reservoir of latently infected cells that evades therapy. To understand the mechanisms of HIV latency, we employed an integrated single-cell RNA-seq/ATAC-seq approach to simultaneously profile the transcriptomic and epigenomic characteristics of ~4000 latently infected cells after reactivation using three different latency-reversing agents (LRAs). Differentially expressed genes and differentially accessible motifs were used to examine transcriptional pathways and transcription factor (TF) activities across the cell population. We identify cellular transcripts and TFs whose expression/activity was correlated with viral reactivation and demonstrate that a machine learning model trained on these data was 68% accurate at predicting viral reactivation. Finally, we validate the role of a new candidate HIV-regulating factor, GATA3, in the viral response to prostratin stimulation. These data demonstrate the power of integrated multimodal single-cell analysis to uncover novel relationships between host cell factors and HIV latency.

microbiology↗

bioRxiv2022

A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV infected cells

Approximately 70% of the HIV-1 latent reservoir originates from infections of CD4 T cells that occur in the months near the time of ART initiation, raising the possibility that interventions during this period might prevent reservoir seeding and reduce reservoir size. We identify class 1 histone deacetylase inhibitors (HDACi) as potent agents of latency prevention. Inhibiting HDACs in productively infected cells caused extended maintenance of HIV expression and this activity was associated with persistently elevated H3K9 acetylation and reduced H3K9 methylation at the viral LTR promoter region. HDAC inhibition in HIV-infected CD4 T cells during effector-to-memory transition led to striking changes in the memory phenotype of infected cells. Proviral silencing is accomplished through distinct activities of HDAC1/2 and HDAC3. Thus HDACs regulate a critical gateway process for HIV latency establishment and are required for the development of CD4 T-cell memory subsets that preferentially harbor long-lived, latent provirus.

molecular biology↗