Robert Sebra

Mar 6, 2025 | nature.com | Manav Kapoor |Ying-Chih Wang |Anthony Esposito |Kimaada Allette |Kristin G. Beaumont |Robert Sebra | +7 more

Human immunodeficiency virus (HIV) infection depletes CD4 T-cells, and long-term persistence of latent virus prevents full clearance of HIV even in the presence of effective antiretroviral therapy (ART), Here we present the HIV-1-induced lineage tracing (HILT) system, a model that irreversibly marks infected cells within a humanized mouse model, which detects rare latently infected cells. Immunodeficient mice transplanted with genetically modified hematopoietic stem cells develop a human immune system, in which CD4 T-cells contain a genetic switch that permanently labels cells infected by HIV-1 expressing cre-recombinase. Through single-cell RNA sequencing of HILT-marked cells during acute infection and post-ART treatment, we identify distinct CD4+ T-cell transcriptional lineages enriched in either active or latent infections. Comparative gene expression analysis highlights common pathways modulated in both states, including EIF2, Sirtuin, and protein ubiquitination. Critical regulators of these pathways, including JUN, BCL2, and MDM2, change to opposite directions in the two states, highlighting gene expression programs that may support HIV persistence across T-cell lineages and states. Characterization of HIV infection at the cellular level is important to understand the molecular forces maintaining the latent reservoir and productive infection in T cells. Here authors describe the pathways that are governing these T cell states across the T lineage via a humanized mouse model allowing precise labeling of the HIV-infected cells coupled to single cell RNA sequencing.

Sep 10, 2024 | nature.com | Jens Chr. Hansen |Yuguang Xiong |Kristin G. Beaumont |Robert Sebra |James Gallo |Marc R. Birtwistle | +5 more

AbstractDrug-induced gene expression profiles can identify potential mechanisms of toxicity. We focus on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced-pluripotent-stem-cell-derived cardiomyocytes, using bulk transcriptomic profiles. We use singular value decomposition to identify drug-selective patterns across cell lines obtained from multiple healthy human subjects.

Jan 19, 2024 | nature.com | Matthew D. Galsky |Sudeh Izadmehr |Edgar Gonzalez-Kozlova |Kevin Chan |Christos E. Kyriakopoulos |Mahalya Gogerly-Moragoda | +5 more

Correction to: Nature Medicine https://doi.org/10.1038/s41591-023-02568-1, published online 2 October 2023. In the version of the article initially published, Diane M.

Oct 2, 2023 | nature.com | Matthew D. Galsky |Sudeh Izadmehr |Edgar Gonzalez-Kozlova |Kevin Chan |Christos E. Kyriakopoulos |Robert M. Samstein | +5 more

AbstractCystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC), but it is life-altering. We initiated a phase 2 study in which patients with MIBC received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) could proceed without cystectomy.