Journal: Nature Immunology

Article Title: TGF-β mediates epigenetic control of innate antiviral responses and SIV reservoir size

doi: 10.1038/s41590-026-02458-x

Figure Lengend Snippet: a , Top: Twenty-eight RMs infected intravenously with SIVmac239. ART (TDF/FTC/DTG) initiated at day 42 post-infection and maintained for 14 months prior to immunotherapeutic interventions. RMs received aIL-10 mAb (red), aIL-10 mAb + aPD-1 mAb (combo, blue) or vehicle (ART-only, black), with infusions every 3 weeks. ATI occurred 12 weeks after first dose of immunotherapy. mAb infusions continued for 14 weeks after ATI. Bottom: Continuous lines represent the median VL per group. A significant reduction in VL was observed by week 36 (combo versus control, P = 0.02; combo versus aIL-10, P = 0.015, two-sided Wilcoxon rank-sum test). Created in BioRender. Pereira Ribeiro, S. https://BioRender.com/g6uf0rn (2026). b , CA-vDNA levels in LNMCs from combo-treated CA-vDNA lo and CA-vDNA hi RMs 24 weeks post-ATI. Two-sided Wilcoxon rank-sum test. Error bars represent mean ± s.e.m. n = 10. c , Module of IFN-related pathways enriched in PBMCs and LNMCs from combo-treated RMs pre-ATI ( P < 0.05) when compared to RMs treated with aIL-10 alone and ART-only controls. Only pairs of pathways with a Jaccard similarity index above 0.25 are represented. Red circles depict the upregulated signaling pathways. Circle size reflects the size of the gene set. d , Volcano plot of the top target genes of IRF1 and IRF7 upregulated in PBMCs/LNMCs of combo-treated RMs compared to controls pre-ATI. e . Volcano plot of the top target genes of STAT1 upregulated in PBMCs/LNMCs of combo-treated RMs compared to controls pre-ATI. D-E. TFs target genes were sourced from CHEA and TRANSFAC databases. Genes in the plots are the union of upregulated genes (FC > 1.3, P < 0.05) in PBMCs/LNMCs from combo-treated RMs compared to controls. A moderated t-test combined with an Empirical Bayes method (eBayes) was used to identify DEGs. f , Heatmap (top) depicting levels of phosphorylated IRF3, IRF7 and STAT1 in immune subsets from LNMCs and PBMCs pre-ATI in combo-treated RMs. Only features significantly different between CA-vDNA hi and CA-vDNA lo RMs (nominal P < 0.05) are shown. Dot plots (bottom) show the raw values of the feature per group. Groups comparison was performed with two-tailed unpaired t -test. Error bars represent mean ± s.e.m. n = 10. g . Heatmap (top) depicting levels of phosphorylated IRF3, STAT3, and IRF7 from PBMCs pre-ATI correlated to CA-vRNA in LNMCs at 24 weeks post-ATI. Smaller heatmap on the right indicate negative correlation (nominal P < 0.05) to virologic readouts. Correlations were calculated with two-sided Spearman correlation method. The boxplots (bottom) show the raw values of features in the heatmap. The central line indicates the median, with hinges at the first and third quartiles and whiskers extending 1.5× interquartile range. Group differences were assessed using regression t‑statistics (FDR P < 0.05), with Holm–Bonferroni correction for multiple comparisons. Control n = 8, aIL-10 n = 9, aIL-10 + aPD-1 n = 10. h . Correlation between levels of phosphorylated IRF7 in CD4 + T CM cells pre-ATI and virologic readouts in plasma (log pVL, copies per ml) and LNMCs (log 10 CA-vRNA, log 10 CA-vDNA, log 10 IPDA and log 10 2-LTR) 24 weeks post-ATI. Two-sided Spearman correlation. Nominal p-values and correlation coefficient (rho) values are shown. i , Left: integrated model from mixOmics R package using flow cytometry and bulk RNA-Seq data pre-ATI. The model negatively correlates with levels of CA-vRNA in LNMCs ( P = 0.0093). A two-sided Spearman correlation (rho) coefficient was calculated per gene-flow cytometry marker interaction (significance P < 0.05). The BH method was used to adjust for multiple comparisons. The network highlighting the model between gene expression data (blue circles) and flow cytometry data (black squares). The thickness of edges represent the correlation coefficient between pairs of markers. Right panel: the bar chart illustrates the strength of the statistical significance of the association between CA-vRNA levels in LNMCs and gene expression data (NES), flow cytometry data and the combination of both. ART, antiretroviral therapy; ATI, analytical treatment interruption; CA-vDNA, cell-associated viral DNA; CA-vRNA, cell-associated viral RNA; DEGs, differentially expressed genes; DTG, dolutegravir; FC, fold change; FTC, emtricitabine; IPDA, intact proviral DNA assay; LNMCs, lymph node mononuclear cells; mAb, monoclonal antibody; NES, normalized enrichment scores; PBMCs, peripheral blood mononuclear cells; RMs, rhesus macaques; SIV, simian immunodeficiency virus; T CM , central memory T cells; TDF, tenofovir disoproxil fumarate; TFs, transcription factors; VL, viral load.

Article Snippet: This study used novel deimmunized aIL-10 (JES3.12G8) and aPD-1 mAbs (1B8 LC3/HC1), which are proprietary reagents developed by Merck & Co.

Techniques: Infection, Control, Protein-Protein interactions, Comparison, Two Tailed Test, Clinical Proteomics, Flow Cytometry, RNA Sequencing, Marker, Gene Expression, Virus