While HIV-1 subtype C (HIV-1C) is the most prevalent and widely distributed subtype in the HIV pandemic, nearly all current prevention and therapeutic strategies are based on work with the subtype B (HIV-1B). HIV-1C displays distinct genetic and pathogenic features from that of HIV-1B. Thus, treatment approaches developed for HIV-1B need to be suitably optimized for HIV-1C. A suitable animal model will help delineate comparative aspects of HIV-1C and HIV-1B infections.
Here, we used a humanized mouse model to evaluate HIV-1C infection, disease progression, response to anti-retroviral therapy (ART) and viral rebound following therapy interruption. A limited comparative study with a prototypical subtype B virus was also performed. Viral infection, immune cell dynamics, acquisition of anti-retroviral therapy (ART) resistance and anatomical reservoir distribution following extended and interrupted therapy were compared.
In comparison, lower early plasma viremia was observed with HIV-1C, but with similar rate of CD4+ T cell depletion as that of HIV-1B. Viral suppression by ART was delayed in the HIV-1C infected group with evidence, in one case, of acquired class wide resistance to integrase inhibitors, a critical component of current global therapy regimens. Also, HIV-1C infected animals displayed faster rebound viremia following ART interruption (ATI). Disparate patterns of tissue proviral DNA distribution were observed following extended ART and ATI suggestive of distinct sources of viral rebound.
In this preliminary study, discernible differences were noted between HIV-1C and B with implications for prevention, therapeutics and curative strategies. Results from here also highlight the utility of the hu-HSC mouse model for future expanded studies in this context.
Copyright © 2025 Kaginkar, Remling-Mulder, Sahoo, Pandey, Gurav, Sutar, Singh, Barnett, Panickan, Akkina and Patel.

Hepatocellular carcinoma (HCC) resists immunotherapy due to its immunosuppressive microenvironment. Sarcoma homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) inhibits T cell receptor signaling, and its pharmacological inhibition is limited by poor selectivity and membrane permeability. Here, we generated CRISPR-edited SHP-1-knockout (KO) CD8+ T cells to enhance adoptive therapy against HCC. Single-cell RNA sequencing of HCC patient T cells revealed elevated SHP-1 in exhausted subsets. SHP-1-KO T cells exhibited increased effector memory T cells (TEM) proportions and enhanced IFN-γ/Granzyme B/perforin secretion, improving cytotoxicity against HCC lines. In humanized PDX models, SHP-1-KO T cells demonstrated superior tumor-killing activity. Transcriptomics identified upregulated lipid metabolism pathways, with HMGCR as a hub gene. Combining SHP-1-KO T cells with simvastatin (HMGCR inhibitor) synergistically amplified anti-HCC efficacy. This study proposes a dual strategy combining SHP-1-targeted cell therapy and metabolic modulation to overcome immunotherapy resistance, offering a translatable approach for HCC treatment.
© 2025 The Author(s).

The DNA damage response (DDR) and the blood-tumor barrier (BTB) restrict chemotherapeutic success for primary brain tumors like glioblastomas (GBMs). Coherently, GBMs almost invariably relapse with fatal outcomes. Here, we show that the interaction of GBM and myeloid cells simultaneously induces chemoresistance on the genetic and vascular levels by activating GP130 receptor signaling, which can be addressed therapeutically. We provide data from transcriptomic and immunohistochemical screens with human brain material and pharmacological experiments with a humanized organotypic GBM model, proteomics, transcriptomics, and cell-based assays and report that nanomolar concentrations of the signaling peptide humanin promote temozolomide (TMZ) resistance through DDR activation. GBM mouse models recapitulating intratumoral humanin release show accelerated BTB formation. GP130 blockade attenuates both DDR activity and BTB formation, resulting in improved preclinical chemotherapeutic efficacy. Altogether, we describe an overarching mechanism for TMZ resistance and outline a translatable strategy with predictive markers to improve chemotherapy for GBMs.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

The clinical success of immune checkpoint inhibitors is compromised by the fact of immune-related adverse events (irAEs), especially for older patients. To identify predictive biomarkers for older patients with irAEs, we used multiplex immunoassay and flow cytometry and liquid chromatography-tandem mass spectrometry to test immune factors and plasma protein and metabolites levels in non-small cell lung cancer (NSCLC) patients. The results showed that older patients with irAEs displayed lower CD28, CD4+ T cell, and B cell and higher interleukin (IL)-10 and CCL2 levels at baseline. Besides, lower aldolase, fructose-bisphosphate B (ALDOB), higher ST6GAL1, and lower lactate/pyruvate ratio at baseline were found in older patients with irAEs. Based on metabolomic markers, predictive models were developed to distinguish patients with grade 2-4 irAEs from grade 0-1 (Area under curve, AUC = 0.831) and to distinguish patients with grade 3-4 irAEs from grade 2 (AUC = 1). Our results confirmed the predictive value of plasma metabolites for irAEs in older patients with NSCLC.© 2024 Published by Elsevier Inc.

Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs). RECs are defined by CD74/CD68 expression, and although derived from leukemic stem cells (LSCs), are devoid of stem/progenitor capacity. Based on REC in situ proximity to CD34-expressing cells identified using spatial transcriptomics on AML patient bone marrow samples, RECs demonstrate the ability to augment or reduce leukemic regeneration in vivo based on transfusion or depletion, respectively. Furthermore, RECs are prognostic for patient survival as well as predictive of treatment failure in AML cohorts. Our study reveals RECs as a previously unknown functional catalyst of LSC-driven regeneration contributing to the non-canonical framework of AML regeneration.
Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.