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Biphasic Decay of Intact SHIV Genomes Following Initiation of Antiretroviral Therapy Complicates Analysis of Interventions Targeting the Reservoir

Kumar et al., PNAS. 2023.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614214/

The latent HIV-1 reservoir persists with antiretroviral therapy (ART), and assays for quantifying intact proviruses in nonhuman primate models are needed. Researchers used a simian–human immunodeficiency virus (SHIV) intact proviral DNA assay to describe viral decay during the first year of ART in female rhesus macaques. Their results suggest that intact SHIV genomes in circulating CD4+ T cells undergo biphasic decay during the first year of ART, with a rapid first phase and a slower second phase. These findings can provide insight for future studies using SHIV models, as well as new cure interventions. Supported by ORIP (R01OD011095) and NIAID.

Large-Scale Production of Human Blastoids Amenable to Modeling Blastocyst Development and Maternal-Fetal Crosstalk

Yu et al., Cell Stem Cell. 2023.

https://www.sciencedirect.com/science/article/abs/pii/S1934590923002850?via%3Dihub=

Human blastoids provide a valuable model to study early human development and implantation with reduced genetic heterogeneity between samples. Investigators reported a protocol for efficient generation of high-fidelity human blastoids from naïve pluripotent stem cells. The similarities between blastoids and blastocysts in signaling activities—demonstrated using single-cell RNA sequencing—support the use of blastoids to model lineage differentiation and cavity formation. Additionally, endometrial stromal effects in promoting trophoblast cell survival, proliferation, and syncytialization during co-culture with blastoids demonstrated the capability to model maternal–fetal crosstalk. The protocol will facilitate broader use of human blastoids as an ethical model for human blastocysts. Supported by ORIP (S10OD028630) and others.

p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy

Faget et al., Cancer Discovery. 2023.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/

This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.