bims-traimu 2026-03-22 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–03–22
thirteen papers selected by
Yantong Wan, Southern Medical University

The type-I interferon priming signal balances antibacterial and antitumor trained immunity in alveolar macrophages.
Revisiting T cells: Innate actions and emerging links to innate memory response.
Respiratory syncytial virus infection induces heterologous protection against SARS-CoV-2 through γδ T cell-mediated trained immunity and the activation of SARS-CoV-2-reactive mucosal T cells.
A glycopeptide hydrogel confers protection and treatment in sepsis via recruitment and training of macrophages.
ACK2 antibody conditioning enhances adoptive transfer of hematopoietic progenitors to study central trained immunity in mice.
Infection, vaccination and risk of dementia: a proposed immunological model.
Spatiotemporal immune gradients in gout: immune response-driven activation of the NLRP3-IL-1β axis and its transition to trained immunity.
Could β-glucans enhance the immune response to SARS-CoV-2 vaccine by inducing trained immunity and boosting neutralizing antibody production?
Scap stabilizes PKM2 to promote glycolysis and enhance anti-fungal immunity in macrophages.
Weaning drives microbiome-mediated epigenetic regulation to shape immune memory in mice.
Estrogen receptor β deficiency increases susceptibility to sepsis through metabolic reprogramming-induced macrophage pyroptosis.
Spatiotemporal molecular profiling of macrophage-fibroblast crosstalk defines checkpoints orchestrating onset and resolution of inflammation.
TGF-β mediates epigenetic control of innate antiviral responses and SIV reservoir size.

Cell Mol Immunol. 2026 Mar 17.

The type-I interferon priming signal balances antibacterial and antitumor trained immunity in alveolar macrophages.

Tao Wang, Jinjing Zhang, Ying Li, Yuxuan Miao, Yanling Wang, Lu Wang, Yuanyuan Liu, Chia-Wei Chang, Enguo Chen, Yushi Yao.

  Tissue-resident macrophages may be trained to confer an enhanced response to heterologous restimulation and thus foster versatile trained immunity (TI) against both infections and tumors. However, the key priming signals that contribute to such functional versatility in trained macrophages are not fully understood. Here, we show that influenza A virus (IAV) infection in mice induces lasting transcriptional imprints of acute type-I interferon (IFN-I) signaling in lung-resident alveolar macrophages (AMs) that confer balanced antibacterial and antitumor TI responses. In both IAV-infected mice and an ex vivo cytokine-mediated training system, IFN-I signaling is critical for the development of antitumor TI functions, although it limits antibacterial TI functions in AMs. Moreover, human AMs carrying transcriptional imprints of IFN-I signaling are associated with immune activation in lung cancer tissues. Our findings highlight IFN-I as a key priming signal required for the development of versatile TI functions in AMs with balanced antibacterial and antitumor potential.

Keywords:  Trained immunity; alveolar macrophages; influenza; innate immune memory; type-I interferon

DOI:  https://doi.org/10.1038/s41423-026-01397-9
J Immunol. 2026 Mar 17. pii: vkag001. [Epub ahead of print]215(3):

Revisiting T cells: Innate actions and emerging links to innate memory response.

Kim A Tran, Maziar Divangahi.

  The traditional view of the immune system distinguishes between the innate immune system, which serves as the host's first line of defense against pathogens, and the adaptive immune system, which evolved to manage more complex or recurrent infections. However, the discovery of evolutionarily conserved mechanisms in innate memory cells (trained immunity) has revealed adaptive-like characteristics in innate immune cells, challenging the conventional dogma between innate and adaptive immunity. Simultaneously, growing evidence shows that T cells exhibit innate-like features. In this review, we explore unconventional T cells (γδ cells, natural killer T cells, mucosal-associated invariant T cells) and conventional αβ T cells (virtual memory, memory T cells) to emphasize the broad spectrum of beneficial effects that the adaptive immune system can particularly exert in early host defense strategies, including innate immune memory. These mechanisms confer clear advantages for immune protection and homeostasis, especially during early childhood, and provide a new perspective on canonical immune functions.

Keywords:  T cells; innate-like T cells; memory; trained immunity

DOI:  https://doi.org/10.1093/jimmun/vkag001
J Virol. 2026 Mar 18. e0165825

Respiratory syncytial virus infection induces heterologous protection against SARS-CoV-2 through γδ T cell-mediated trained immunity and the activation of SARS-CoV-2-reactive mucosal T cells.

Awadalkareem Adam, Wenzhe Wu, Madison C Jones, Haiping Hao, Aditi, Parimal Samir, Xiaoyong Bao, Tian Wang.

  Respiratory viruses can infect hosts concurrently or sequentially, potentially influencing each other's pathogenic trajectory. However, the underlying immune mechanisms governing these interactions remain poorly understood. In this study, we examined whether respiratory syncytial virus (RSV) infection modulates host susceptibility to subsequent SARS-CoV-2 infection using two murine models. We found that prior RSV infection conferred dose- and time-dependent heterologous protection against SARS-CoV-2. Transcriptomic and immunological analyses revealed that RSV activated lung antigen-presenting cells (APCs) and SARS-CoV-2-reactive mucosal T cells by day 9 post-infection, with responses waning by 1 month. RSV also promoted expansion of pulmonary γδ T cells and upregulation of their metabolic pathways. Notably, RSV-infected TCRδ⁻/⁻ mice, which lack γδ T cells, exhibited diminished SARS-CoV-2-reactive mucosal T cell responses, elevated viral loads, and exacerbated lung inflammation following SARS-CoV-2 challenge compared to wild-type controls. These findings suggest that RSV infection induces γδ T cell-mediated trained immunity and primes mucosal T cell responses, thereby providing heterologous protection against SARS-CoV-2.IMPORTANCEThe mechanisms by which prior respiratory viral infections confer heterologous protection remain largely undefined. In this study, we investigated whether respiratory syncytial virus (RSV) infection influences host susceptibility to subsequent SARS-CoV-2 infection in mice. We found that prior RSV exposure conferred dose- and time-dependent heterologous protection against SARS-CoV-2. Mechanistically, RSV infection induces γδ T cell-mediated trained immunity, enhances antigen-presenting cell activation, and promotes the generation of SARS-CoV-2-reactive mucosal T cells. Together, these immune responses contribute to cross-protective immunity against SARS-CoV-2. Our findings offer new insights into the immunological interplay between co-circulating respiratory viruses and SARS-CoV-2, with implications for future vaccine design and pandemic preparedness.

Keywords:  RSV; SARS-CoV-2; trained immunity; γδ T cells

DOI:  https://doi.org/10.1128/jvi.01658-25
Mater Today Bio. 2026 Apr;37 102989

A glycopeptide hydrogel confers protection and treatment in sepsis via recruitment and training of macrophages.

Lanbing Zou, Baixue Fu, Dianyu Wang, Yanbin Chen, Han Gui, Ganen Mu, Xinyi Li, Yumin Zhang, Jianfeng Liu, Cuihong Yang.

  Sepsis is a critical global health challenge, characterized by dysregulated host responses and high mortality rates. Current treatment therapies inadequately address persistent immunoparalysis and adverse reactions, leaving survivors susceptible to recurrent infections. Herein, we developed the first β-glucan (BG) delivery system using self-assembling peptide hydrogels to combat immuneparalysis associated with sepsis. This hydrogel combines oxidized BG (BGA) and tuftsin-functionalized self-assembling peptides (t-RADA16) to create an injectable glycopeptide hydrogel (BGA@t-RADA16). Upon subcutaneous injection, the hydrogel forms a dual-functional platform consisting of a "sustained-release depot" of BGA and a local "trained immunity center", where the three-dimensional network of peptide nanofibers actively recruits macrophages and the BGA educates them in-situ. This endows the macrophages with an immune memory function, generating a rapid and powerful defense against secondary infection, and forming a "targeted-sustained-response" cascade treatment system. The results demonstrate that the glycopeptide hydrogel reduces organ damage, lowers sepsis mortality and confers protection against secondary infections by coordinating the activation of both innate and adaptive immune pathways. Furthermore, BGA-P@t-RADA16 simultaneously clears acute-phase pathogens and provides long-term immune training by loading polymyxin B within a single system, which truly addresses the problem of "immune imbalance" in the pathological process of sepsis. BGA@t-RADA16 provides a new tool for sepsis immunotherapy, pioneering an integrated strategy of "immune training, acute intervention and long-term defense". This strategy is expected to be an important breakthrough in the treatment of sepsis and related immune disorders.

Keywords:  Glycopeptide; Hydrogel; Sepsis immunotherapy; Trained immunity; β-glucan

DOI:  https://doi.org/10.1016/j.mtbio.2026.102989
Front Immunol. 2026 ;17 1735878

ACK2 antibody conditioning enhances adoptive transfer of hematopoietic progenitors to study central trained immunity in mice.

Andrea Guiu, Paula Guerrero, María Sobén, Daniel Gozalbo, M Luisa Gil, Alberto Yáñez.

  Hematopoietic stem and progenitor cell (HSPC) transplantation is a cornerstone for studying hematopoiesis. However, classical conditioning regimens such as irradiation or chemotherapy induce strong inflammation, alter the bone marrow (BM) microenvironment, and severely limit the interpretation of differentiation processes. Moreover, donor HSPC engraftment efficiency in immunocompetent recipients without conditioning is usually very low. In this work, we produced and purified the monoclonal anti-c-Kit antibody ACK2 and tested its capacity to transiently deplete HSPCs in immunocompetent C57BL/6 mice. We defined the in vivo clearance kinetics of the ACK2 antibody from serum, identified the optimal transplantation window, and evaluated donor engraftment efficiency. Intraperitoneal injection of ACK2 induced transient HSPC depletion in the BM, with maximal depletion and complete clearance of circulating antibody at day 4 post-injection. Transplantation of donor HSPCs in ACK2-conditioned recipients at this time point resulted in significantly improved engraftment compared to PBS-treated recipients, particularly in the BM. As a proof of concept, we applied this mouse model to investigate properties of innate immune memory in HSPCs exposed to Candida albicans in vivo. For this, we adoptively transferred HSPCs from infected mice with a non-virulent C. albicans strain and assessed the functional properties of their derived neutrophils in vivo. We found that neutrophils derived from C. albicans-exposed HSPCs displayed an enhanced recruitment to the peritoneal cavity during a secondary C. albicans infection compared to control HSPC-derived neutrophils. In conclusion, here we describe a non-inflammatory, antibody-based conditioning method that enhances adoptive transfer of HSPCs in immunocompetent mice. Consistent with previous reports, ACK2-based conditioning alone does not enable permanent hematopoietic engraftment, but rather facilitates transient donor cell engraftment which provides a versatile methodological tool to study the biology and functional programming of exogenous HSPCs in vivo, including their contribution to trained immunity.

Keywords:  ACK2; adoptive transfer; antibody; c-kit; central trained immunity; hematopoietic progenitor; neutrophils

DOI:  https://doi.org/10.3389/fimmu.2026.1735878
Front Immunol. 2026 ;17 1748535

Infection, vaccination and risk of dementia: a proposed immunological model.

Justin Devine, Bart Jacobs, Isabel Leroux-Roels, Geert Leroux-Roels, Robbert van der Most.

  With ageing populations, the prevalence of different types of dementias is increasing. The pathology of Alzheimer's disease (AD), the most common form of dementia, has been linked to the presence of plaques and neurofibrillary tangles in the central nervous system of patients. There are growing indications that risk of developing dementia correlates with several infectious agents, including human herpes viruses, flaviviruses and SARS-CoV-2. This has led to a proposition that AD and other dementias could be considered as having an infectious disease etiology. Whilst the mechanisms behind this remain unclear, intriguing epidemiological data suggest that several vaccinations are correlated with reduced risk for dementia. Intravesicular administration of the tuberculosis vaccine strain Bacille Calmette-Guérin (BCG) has been associated with decreased risk of dementia in bladder cancer patients. This has led to the hypothesis that non-specific effects of vaccinations, mediated through trained innate immunity, provide a mechanistic explanation. Over the last few years, the AS01-adjuvanted recombinant shingles vaccine has also been associated with reduced risk in several studies. Moreover, in a recent study, immunization with the adjuvanted RSV vaccine, also containing AS01, was shown to reduce risk of dementia. Integrating data on BCG and mechanistic hypotheses, recent findings on the AS01 adjuvant, and the role of trained innate immunity, we describe here an immunological model that connects vaccine and adjuvant mode of action with risk of dementia. This immunological model can help shape a research roadmap to further elucidate the mechanisms behind the collective epidemiological data.

Keywords:  AS01 adjuvant; BCG - Bacille Calmette-Guérin vaccine; dementia; neuro-inflammation; shingles (herpes zoster) vaccine; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1748535
Front Immunol. 2026 ;17 1776479

Spatiotemporal immune gradients in gout: immune response-driven activation of the NLRP3-IL-1β axis and its transition to trained immunity.

Kang Wang, Jiabin Li, Jing Li, Fan Zeng, Siren Li, Pei Chen, Hui Xiong.

  Gout is a crystal-associated autoinflammatory disease triggered by monosodium urate (MSU) crystals, clinically characterized by recurrent transitions between acute inflammatory flares dominated by innate immunity and a state of "trained immunity" during the remission phase. However, previous studies have mostly focused on single time points or local lesions. Such approaches fail to systematically explain the recurrent nature of acute gout flares and the mechanisms underlying multi-system involvement. By integrating evidence from single-cell and spatial transcriptomics as well as mechanistic investigations, this review systematically summarizes the immunopathological features of gout within a spatiotemporal immune framework. At the temporal level, acute gout flares are driven by innate immune activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3)-interleukin-1β (IL-1β) inflammatory cascade. The inflammation then undergoes self-limited resolution mediated by regulatory T cells (Tregs), M2-polarized macrophages, aggregated neutrophil extracellular traps (aggNETs), and pro-resolving lipid mediators. persistent low-grade activation of monocytes/macrophages can still be observed, sustaining a state of "trained immunity." At the spatial level, integrated evidence indicates an immune gradient across the joint, bone, and circulation, ranging from focal hyper-inflammation to systemic low-grade activation. Based on these findings, we propose a time-window stratified intervention strategy centered on the NLRP3-IL-1β axis, and identify inflammatory markers in the joints, subchondral bone, and peripheral blood as the basis for spatially targeted stratification. These insights provide novel perspectives for shifting gout management from the control of individual flares to recurrence risk management and personalized therapy.

Keywords:  gout; immune response; inflammatory response; precision therapy; spatiotemporal immune gradient; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1776479
Front Immunol. 2026 ;17 1675094

Could β-glucans enhance the immune response to SARS-CoV-2 vaccine by inducing trained immunity and boosting neutralizing antibody production?

Márjorie de Assis Golim, Patrícia Valério Orlandi Falbo, Aline Márcia Marques Braz, Rafael Plana Simões, Rejane Maria Tommasini Grotto, Beatriz Furtado Pegatin, Jaime Olbrich-Neto, Rui Seabra Ferreira.

  β-Glucans stimulate the immune system, training it to recognize and respond to antigens, which bolsters immunity, including to vaccines. The present study evaluated the capacity of β-glucans to stimulate immunity subsequent to primary vaccination for SARS-CoV-2 with ChAdOx1. Thirty-four SARS-CoV-2-non-immune men (18-49 years) were split into two groups: one receiving 500 mg of oral insoluble yeast β-glucans daily (the glucan group) and the other a placebo (the control group). The supplementation period lasted fourteen days in total, including seven days before and seven days after the initial vaccine dosage. A series of blood samples were collected at three time points: M1 (prevaccination); M2 (30 days after the first vaccination); and M3 (30 days after booster). A lateral flow immunoassay was used to qualitatively identify IgM and IgG against the virus. The levels of antigen-specific IgG anti-spike (S1), receptor-binding domain (RBD), and nucleocapsid (N) were quantified using a LEGENDplex assay. The NeutraLISA assay was used to evaluate the neutralizing antibodies (NAbs). Statistically significant results were defined as those with p < 0.05. Both groups produced similar amounts of NAbs after the first vaccination (M2). However, the glucan group had higher levels in M3, with a more uniform distribution. Furthermore, the levels of anti-S1 IgG in M2 exhibited elevated concentrations, indicating a significant positive correlation with NAbs levels obtained post-second dose (M3). In contrast, individuals who had immunity to common cold human coronaviruses (HCoVs), evidenced by the presence of IgG anti-N in M1 were associated with IgG anti-S1 only in M3, not correlated with NAbs levels. This finding indicates that cross-immunity from other HCoVs did not accelerate or direct the humoral immune response as was observed in the glucan group. Therefore, it can be inferred that the β-glucan supplementation was more effective than immunity from other HCoVs. The capacity of β-glucan to induce trained immunity (TRIM) has the potential to augment immune responses, thereby modifying antibody production in response to the vaccine stimulus. Future studies should evaluate the potential of β-glucan as an adjuvant to vaccines, especially in children, the elderly, and immunocompromised individuals. They should also assess long-term immunity and cross-protection.

Keywords:  Covid-19; SARS-CoV-2; beta-glucans; trained immunity; vaccines

DOI:  https://doi.org/10.3389/fimmu.2026.1675094
Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00184-1. [Epub ahead of print]45(3): 117106

Scap stabilizes PKM2 to promote glycolysis and enhance anti-fungal immunity in macrophages.

Jiaqi Huang, Yuejue Wang, Fei Li, Nan Zhang, Guoxiong Tian, Dongyu Guo, Yanqi Guo, Zhengyuan Liu, Yinfang Wu, Xiaoping Li, Fei Xu, Zhongnan Qin, Ruixin Jia, Lingling Dong, Shenwei Gao, Jinkang Yu, Jian Lou, Songmin Ying, Daniel H Scharf, Wen Li, Zhihua Chen.

  Fungal infection induces substantial but poorly understood metabolic reprogramming in macrophages. We demonstrate that fungal stimulation reduces Scap levels in human monocytes and murine bone-marrow-derived macrophages (BMDMs), and Scap deficiency impairs cytokine production and phagocytosis, leading to more severe fungal infections. Although Scap canonically regulates lipid synthesis, pharmacological inhibition of lipid synthesis and genetic ablation of SREBP1/2 reveal that Scap-dependent anti-fungal immunity is largely independent of this pathway. Instead, Scap interacts with and stabilizes PKM2, a key glycolysis enzyme, by competitively inhibiting STUB1-mediated ubiquitination and degradation of PKM2 at Lys-311. PKM2 agonist DASA58 enhances fungus-induced production of pro-inflammatory cytokines and phagocytic activity in wild-type BMDMs and partially rescues these functions in Scap-deficient macrophages, whereas myeloid-specific deletion of PKM2 recapitulates the effects of Scap deficiency. These results identify Scap as a critical regulator of PKM2-mediated glycolysis and demonstrate its potential as a therapeutic target for modulation of anti-fungal immunity.

Keywords:  CP: immunology; CP: metabolism; PKM2; STUB1; Scap; anti-fungal immunity; glycolysis; macrophages; phagocytosis; ubiquitination

DOI:  https://doi.org/10.1016/j.celrep.2026.117106
Nat Microbiol. 2026 Mar 19.

Weaning drives microbiome-mediated epigenetic regulation to shape immune memory in mice.

Li Yang, Robert C Peery, Shirui Zhou, Xiaomin Chen, Leah M Farmer, Fabiola Gutierrez, Stephanie Fowler, Lanjing Zhang, Julia M Salamat, Karen Riggins, Jiejun Shi, Lanlan Shen.

During weaning, the transition to solid food diversifies the gut microbiome, triggering a programmed immune response critical for long-lasting mucosal immunity. Previous work showed that the gut microbiome mediates epigenetic development in intestinal stem cells (ISCs) during suckling, but what happens during weaning is unclear. Here, genome-wide profiling revealed that weaning-driven microbiome changes shape the DNA methylome and transcriptome of murine ISCs in an IFNγ-dependent manner. Specifically, we observe demethylation of enhancer elements essential for MHC class II genes, which results in a transcriptional memory that persists through differentiation into adulthood. IFNγ blockade, or low-dose penicillin to target Gram-positive bacteria, in early life impaired microbiome-mediated epigenetic control and mucosal immunity, and exacerbated colitis. Murine organoids primed with IFNγ showed rapid, amplified transcriptional responses upon secondary stimulations. These findings reveal that early-life events alter the gut microbiome and these changes reprogramme ISC epigenetic memory to shape mucosal immunity.

DOI: https://doi.org/10.1038/s41564-026-02295-6
J Clin Invest. 2026 Mar 17. pii: e196636. [Epub ahead of print]

Estrogen receptor β deficiency increases susceptibility to sepsis through metabolic reprogramming-induced macrophage pyroptosis.

Yanrong Zhu, Gang Li, Yilei Guo, Yue He, Wanyi Zhang, Lei Gao, Jing Zhang, Pengxiang Guo, Haochang Lin, Wenjie Zhang, Zhifeng Wei, Yufeng Xia, Yue Dai.

  Understanding susceptibility factors of sepsis is crucial for early diagnosis and development of personalized treatment strategies. However, the genetic determinants for initiation and progression of sepsis remain unclear. Here, we showed that the expression levels of estrogen receptor (ER) β are significantly reduced in the peripheral blood of sepsis patients, which were negatively correlated with disease severity. The results from human samples and experimental animals demonstrated that ERβ deficiency enhances the body's susceptibility to sepsis by inducing macrophage pyroptosis, thereby impairing bacterial clearance. Mechanistically, ERβ deficiency enhanced fatty acid oxidation, increased acetyl-CoA levels, and promoted acetylation of stomatin-like protein 2 (Stoml2) at K221, leading to mitochondrial dysfunction and macrophage pyroptosis. Mutating the Stoml2 K221 site mitigated these effects and improved survival of septic mice. These findings suggest ERβ deficiency as a potential genetic factor in sepsis susceptibility.

Keywords:  Immunology; Inflammation; Macrophages

DOI:  https://doi.org/10.1172/JCI196636
Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00169-5. [Epub ahead of print]45(3): 117091

Spatiotemporal molecular profiling of macrophage-fibroblast crosstalk defines checkpoints orchestrating onset and resolution of inflammation.

Katharina Weishaupt, David Chambers, Maria Dzamukova, Ivana Androšević, Jean-Philippe Auger, Darleen Hueser, Sébastien Trzebanski, Andreas Ramming, Anika Grüneboom, Georg Schett, Steffen Jung, Markus H Hoffmann, Gerhard Krönke.

  The molecular details of macrophage-fibroblast crosstalk during the onset and resolution of inflammatory disease remain incompletely understood. Here, we apply a bioinformatic modeling approach based on single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing to map heterocellular signaling circuits of synovial macrophage and synovial fibroblast (SF) subsets during various stages of inflammatory arthritis. While SFs function as key pacemakers of synovial inflammation, individual subsets of synovial macrophages support both the perpetuation and the resolution of arthritis. Pro-inflammatory Il1b+ macrophages dominate the early stages of inflammation and retain a substantial intrinsic plasticity that is characterized by chromatin remodeling and an eventual differentiation into Spp1+ macrophages. These cells display a terminally differentiated phenotype, suppress the activation of pro-inflammatory SFs, and initiate the resolution of arthritis by secretion of regulatory mediators, including osteopontin. Our data highlight the dichotomous character of macrophage-fibroblast crosstalk and define the cellular and molecular checkpoints that control the onset and resolution of immune-mediated inflammatory diseases.

Keywords:  CP: immunology; arthritis; crosstalk; fibroblasts; inflammation; macrophages; osteopontin

DOI:  https://doi.org/10.1016/j.celrep.2026.117091
Nat Immunol. 2026 Mar 20.

TGF-β mediates epigenetic control of innate antiviral responses and SIV reservoir size.

Khader Ghneim, Felipe Ten-Caten, Ana Carolina Santana, Muhammad Bilal Latif, Diego Andres Diaz-Dinamarca, Tamara García-Salum, Perla Mariana Del Rio Estrada, Puja Sohal, Zachary Strongin, Justin Harper, Sherrie Jean, Chelsea Wallace, Robert Balderas, Jeffrey D Lifson, Gopalan Raghunathan, Eric Rimmer, Cinthia V Pastuskovas, Guoxin Wu, Luca Micci, Luiz Felipe Martins Sieben, Pedro Cesar Lopes Gerum, Jessica Dos Santos, Mihai G Netea, Andre van der Ven, Guido Silvestri, Daria J Hazuda, Daniel M Gorman, Bonnie J Howell, Ashish A Sharma, Mirko Paiardini, Hugo Soudeyns, Susan Pereira Ribeiro, Rafick P Sekaly.

Immune interventions toward an HIV cure have focused on rejuvenating adaptive immune responses. Herein we provide a framework that features epigenetic programming of myeloid and CD4+ T cells as a major mechanism that promotes decay of the HIV reservoir. Coordinate regulation of gene expression and chromatin accessibility of pathways of innate antiviral immunity was associated with decay of cell-associated viral DNA (CA-vDNA) following analytical treatment interruption in simian immunodeficiency virus-infected rhesus macaques (RMs) treated with anti-IL-10 and anti-PD-1. TGF-β/SMAD signaling in a subset of combo-treated CA-vDNAhi RMs, suppressed this antiviral activity through histone deacetylases, reducing chromatin accessibility of interferon regulatory factors (IRFs) and STATs. Addition of HDAC inhibitors in vitro restored antiviral response in the presence of TGF-β. Induction of IL-6 in CA-vDNAlo RMs amplified the antiviral network through IRF9. We identified an overlapping molecular cascade in HIV elite controllers, who maintain small HIV reservoirs without antiviral treatment. These data provide insights into strategies for HIV cure interventions.

DOI: https://doi.org/10.1038/s41590-026-02458-x