Persistent HIV-1 reservoirs remain a major barrier to a durable functional cure despite long-term suppressive antiretroviral therapy. Although resting memory CD4+ T cells constitute the best-characterized cellular reservoir, tissue microenvironments shape viral persistence and immune clearance. The rectal mucosa represents a specialized tissue niche containing HIV-susceptible target cells, antigen-presenting cells, microbial products, inflammatory cues, and local metabolic signals. Within this setting, myeloid-lineage cells, particularly tissue-resident macrophages and dendritic cells, may contribute to HIV-1 persistence through mechanisms distinct from classical T-cell latency. Here, we review how rectal mucosal macrophages may support HIV-1 persistence through longevity, resistance to apoptosis, metabolic adaptation, epigenetic regulation, and sequestration of virions within virus-containing compartments. We also discuss the dual role of mucosal dendritic cells as sentinels that capture and transfer HIV-1 to CD4+ T cells, while considering the limited evidence for inducible proviral persistence in selected anatomical and cellular contexts. Importantly, we further distinguish bona fide reservoir-bearing cells from reservoir-supportive mechanisms, including viral capture, trans-infection, immune suppression, and niche-mediated protection. We also highlight how mucosal dysbiosis, barrier disruption, microbial metabolites, chronic interferon signaling, and immunoregulatory myeloid programs may stabilize HIV-1 persistence in rectal tissues. Integrating intact proviral assays, functional measurements, single-cell profiling, multiplex imaging, and spatial transcriptomics will be critical for defining myeloid-associated persistence and guiding tissue-targeted HIV-1 cure strategies.

BackgroundHIV-1 persistence in anatomical reservoirs remains the primary obstacle to a functional cure, even under suppressive antiretroviral therapy (ART). While gut-associated lymphoid tissue (GALT) is a well-recognized site of viral sequestration, the role of adipose tissue as an immunometabolic sanctuary, and its distinct host immune environment compared with peripheral blood remain under-characterized.MethodsIn this study, we quantified the HIV-1 DNA reservoir using droplet digital PCR (ddPCR) in rectal tissues and subcutaneous adipose tissues (SAT), each paired with matched peripheral blood mononuclear cells (PBMCs) from ART-treated individuals. To characterize the host transcriptomic landscape associated with viral persistence, RNA-seq was performed across these compartments. An external healthy human tissue dataset (GSE120795) was integrated to perform background-identity filtering. Key differentially expressed signatures and enriched pathways were further validated using RT-qPCR and Western blot.ResultsThe ddPCR analysis confirmed significantly higher viral DNA loads in both rectal and adipose tissues relative to matched PBMCs, identifying them as major anatomical reservoirs. Transcriptomic profiling after background filtering revealed divergent host responses: rectal reservoirs were primarily characterized by extracellular matrix (ECM) reorganization and epithelial barrier dysfunction, whereas SAT exhibited prominent dysregulation in cell cycle progression and immunometabolic signaling. Notably, cross-tissue enrichment analysis identified the PI3K-Akt signaling pathway as a common transcriptomeic feature across these anatomical sites. Validation experiments confirmed that fibrosis-associated hub gene COL1A1 and the leukocyte recruitment marker CX3CR1 exhibited tissue-specific expression patterns at both mRNA and protein levels compared with PBMCs.ConclusionOur study provides a comprehensive landscape of tissue-specific transcriptomic remodeling in rectal and adipose HIV-1 reservoirs. These findings suggest that persistent viral sequestration is associated with distinct microenvironmental alterations, ranging from fibrotic shifts to metabolic dysregulation, which share common molecular features such as potentially linked to the PI3K-Akt axis. This work underscores the importance of targeting anatomical sanctuaries beyond the peripheral blood in future HIV-1 cure strategies.

Recent studies have demonstrated the pivotal role of pathogenic Th17 cells during the target organ damage in systemic lupus erythematosus (SLE). Therefore, identifying Th17-related precision therapeutic targets is essential for developing effective treatments. Potential targets of a novel alkaloid compound, Dehydrocorydaline (DHC), in SLE were investigated using integrated network pharmacology and molecular docking. The therapeutic efficacy of DHC was evaluated in vivo using a lupus-prone mouse model and in vitro via pathogenic Th17 polarization assays. Mechanistic studies were conducted using transcriptional analysis, cell thermal shift assay (CETSA), microscale thermophoresis (MST), and chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR). This study demonstrates the therapeutic potential of DHC in SLE. Network pharmacology analysis identified mTOR signaling and Th17 cell polarization as key potential targets and pathways of DHC. In vivo, DHC treatment selectively reduced the frequencies of Th17 cells, inhibited serum IL-17A levels, restored glomerular filtration rate (GFR), and attenuated renal damage in lupus mice. Molecular docking, CETSA, and MST results suggested a direct interaction between DHC and mTOR. In vitro, DHC inhibited the phosphorylation of mTOR and STAT3 during pathogenic Th17 differentiation. Pharmacological activation of mTOR reversed the inhibitory effects of DHC on STAT3 activation and Th17 differentiation. Mechanistically, DHC blocked the mTOR-dependent STAT3 nuclear translocation and Rorc transcription during Th17 polarization. DHC attenuates renal damage in SLE by suppressing the Th17 response via the mTOR/STAT3/RORγt axis. This finding represents a novel therapeutic strategy for addressing the unmet clinical needs in SLE.

Cyclic GMP–AMP synthase (cGAS) is a key cytosolic DNA sensor that triggers antiviral immunity by generating the second messenger cyclic GMP–AMP (cGAMP) upon binding to double-stranded DNA. While numerous mechanisms have been shown to restrain cGAS activity, its posttranslational regulation remains incompletely understood. Here, we identify the receptor tyrosine kinase Eph receptors B2 (EPHB2) as a negative regulator of DNA virus–induced immune responses. During viral infection, phosphorylation of EPHB2 by spleen-associated tyrosine kinase (SYK) promotes the direct phosphorylation of cGAS at Tyr483 and Tyr510, thereby facilitating the recruitment of the E3 ubiquitin ligase MARCH8 and the autophagy adaptor p62, which mediate selective autophagic degradation of cGAS. Myeloid-specific EphB2 deletion enhances HSV-1 clearance and markedly improves mouse survival. Given its high expression in the nervous system, we further show that neuronal EPHB2 limits antiviral immunity, as its loss in human neuronal cells or neuron-specific knockout mice enhances cGAS–STING signaling and protects against herpes simplex virus 1 (HSV-1) infection. Moreover, a newly identified small-molecule EPHB2 inhibitor, Q-1-28, restores cGAS levels, amplifies antiviral cytokine production, and protects mice from HSV-1–induced lethality. Together, our findings reveal a phosphorylation-dependent mechanism governing cGAS degradation and establish EPHB2 as a potential therapeutic target for host-directed antiviral intervention.

ABSTRACT Lipid nanoparticle (LNP)–enabled messenger RNA (mRNA) vaccines hold great promise for cancer immunotherapy, yet their clinical translation is often limited by insufficient delivery to secondary lymphoid organs and limited immune activation. Here, we design a redox‐responsive, all‐trans‐retinoic acid (ATRA)–functionalized PEG lipid (ATRA‐SS‐PEG, ASP) as a functional alternative to conventional DMG‐PEG for LNP formulation. ASP incorporation preserves LNP colloidal stability while promoting spleen‐oriented mRNA expression and efficient cytosolic release through intracellular redox‐triggered PEG shedding. Mechanistic comparison with a non‐cleavable ATRA‐PEG analogue confirms the functional contribution of the disulfide linkage to lysosomal escape and mRNA expression. ASP‐LNPs enhance splenic antigen expression, presentation, and immune activation, thereby reprogramming the splenic immune microenvironment toward effective immune priming. Notably, ASP‐LNPs maintain robust mRNA expression upon repeated administration, suggesting improved repeat‐dosing performance. As a proof of concept, ASP‐LNPs encoding ovalbumin (OVA) elicit potent antitumor immunity in B16‐OVA melanoma and pulmonary metastasis models, promoting effector T‐cell infiltration and suppressing tumor progression with a favorable safety profile. Collectively, this work establishes a spleen‐targeted and immunomodulatory LNP platform that integrates stimulus‐responsive cytosolic release with the intrinsic adjuvant activity of ATRA‐conjugated lipids, providing a versatile paradigm for next‐generation mRNA cancer vaccines.

Dendritic cells (DCs) regulate both innate and adaptive immunity during sepsis. Prostaglandins (PGs), small lipid molecules derived from arachidonic acid via COX enzymes, are crucial regulators of immune homeostasis and inflammation. However, their role in sepsis pathogenesis remains poorly defined. In this study, we identified a significant negative correlation between DC depletion and disease severity in patients with sepsis. Thromboxane (TX) A2 receptor (TP) expression was markedly reduced in the blood DCs of patients with sepsis. Patients with low DC-TP expression presented increased blood neutrophil counts and worsened disease severity. In murine models of sepsis induced by cecal ligation and puncture and lipopolysaccharide challenge, DC-specific TP deficiency exacerbated sepsis by promoting S100a8/a9-mediated neutrophil recruitment and, subsequently, neutrophil extracellular trap (NET) formation and lung injury. Genetic and pharmacological inhibition of the S100a8/a9-TLR4 axis protected TP-deficient mice from fatal sepsis. Mechanistically, TP signaling suppressed S100a8/a9 expression in DCs via PKCδ-Stat1 signaling, thereby restricting neutrophil infiltration and NET formation. Finally, the targeted activation of TP in DCs via the nanodrug DCpep-U-46619 effectively alleviated sepsis-induced lung injury in mice. These findings establish TP as a critical immunoregulatory receptor in DCs, highlighting its potential as a therapeutic target for sepsis.

BCL6 is a master regulator of germinal center (GC) B cells. Further identification and characterization of factors that may play a role within the BCL6 network is important for our understanding of GC B cell differentiation and function. Here, through co-Immunoprecipitation coupled with mass spectrometry, we identify CHAF1B as a new partner in the BCL6 complex, which is highly expressed in GC B cells, promoting GC formation and humoral immunity. Loss of CHAF1B impairs the dark zone (DZ) and light zone (LZ) organization and induces apoptosis, resulting in abnormal GC responses and antibody production. Mechanistically, CHAF1B stabilizes BCL6/TBL1XR1 complex to promote GC B cell differentiation by cooperative transcriptional repression. Furthermore, overexpression of CHAF1B in B cells reduces the plasmablast by extending GC reaction, which is positively related to the production of high affinity antibodies in response to vaccines or pathogens. These findings not only advance the understanding of GC biology but also had potential implications for developing targeted strategies to improve vaccination efficacy.

ABSTRACT The persistence of latent HIV-1 reservoirs remains a critical barrier to cure. Current “shock and kill” strategies are limited by ineffective latency-reversing agents (LRAs) and poor understanding of epigenetic regulation. Here, we identify chromatin assembly factor 1 subunit A (CHAF1A), a histone chaperone enforcing HIV-1 latency, as a therapeutic target regulated by antagonistic post-translational modifications: ubiquitination promotes its degradation, while O-GlcNAcylation stabilizes it. We demonstrate that trifluridine, a Food and Drug Administration-approved antiviral drug, reactivates latent HIV-1 by disrupting O-GlcNAcylation, triggering CHAF1A ubiquitination and proteasomal degradation. Notably, CHAF1A expression increases with age in CD4+ T cells (>60 years), correlating with deeper proviral reservoirs. This age-dependent accumulation inversely associates with reduced O-GlcNAcase levels, suggesting O-GlcNAcylation-mediated stabilization in aging. Our findings establish CHAF1A as both a therapeutic target and an age-stratifying biomarker, advancing trifluridine as a translatable LRA to enhance reservoir clearance in aging populations—a demographic increasingly impacted by HIV-1 persistence.IMPORTANCEHIV-1 latency continues to represent a significant barrier to achieving a cure, particularly in aging populations characterized by expanded viral reservoirs and compromised immune recovery—a challenge further intensified by the absence of therapies specifically designed to target age-related mechanisms. Current latency-reversing agents (LRAs) are insufficient in addressing the metabolic and epigenetic dysregulation that sustains viral persistence in older individuals. In this study, we reveal a dynamic interplay between ubiquitination and O-GlcNAcylation that regulates the stability of CHAF1A, a histone chaperone essential for maintaining HIV-1 latency. We identify trifluridine as a novel LRA capable of disrupting O-GlcNAcylation to degrade CHAF1A, thereby effectively reversing latency in primary cells. This research bridges a critical gap between fundamental virology and clinical gerontology. These findings establish a robust foundation for refining strategies aimed at HIV-1 eradication, with a focus on targeting host metabolic-epigenetic networks to address latency in underserved aging populations.

Background Early childhood caries (ECC) has been proposed to be associated with various microorganisms and metabolites. This study aims to compare the prevalence of specific microbial species and salivary metabolomics profile in children with and without ECC, and to explore the correlation between salivary metabolites and targeted microbes. Method Five ml of unstimulated saliva was collected from 32 ECC and 22 caries-free children. Clinical indexed were recorded and questionnaires regarding oral health and dietary habits were obtained from the guardians. The presence of eight specific microbial species were examined using species-specific quantitative PCR (qPCR). Untargeted metabolomics was analyzed to identify key differential metabolites and pathways. Correlations among clinical, microbial, and metabolomic data were further explored. Results The prevalence of Scardovia wiggsiae (90.6%, P < 0.001), Streptococcus mutans (43.8%, P = 0.006), Streptococcus sobrinus (62.5%, P < 0.001), Ligilactobacillus salivarius (93.6%, P = 0.01) and Candida albicans (56.3%, P < 0.001) were significantly higher in the ECC group. The prevalence of ECC was higher in children with two targeted species present compared with children with one targeted species. Histidine metabolism and branched-chain amino acids degradation were activated in ECC group, while glyoxylate and dicarboxylate metabolism, purine and pyrimidine metabolism were inhibited. Histidine and glutathione metabolism was activated with enrichment of targeted microbial species, while linoleic acid metabolism and biotin metabolism was inhibited. The duration of each toothbrushing was a significant risk factor for ECC experience. Conclusion The prevalence of Scardovia wiggsiae, Streptococcus mutans, Streptococcus sobrinus and Candida albicans is higher in ECC children compared to caries-free children. Oral habits and salivary metabolites also vary between ECC and caries-free children.

HIV-1 Tat acts as a central molecular switch governing the transition between viral latency and active replication, making it a pivotal target for HIV-1 functional cure strategies. By binding to the viral long terminal repeat (LTR) and hijacking host transcriptional machinery, Tat dynamically regulates RNA polymerase II processivity to alter viral transcription states. Recent studies reveal its context-dependent variability: while Tat recruits chromatin modifiers and scaffolds non-coding RNAs to stabilize epigenetic silencing in latently infected cells, it also triggers rapid transcriptional amplification upon cellular activation. This review systematically analyzes the bistable regulatory mechanism of Tat and investigates advanced technologies for reprogramming this switch to eliminateviral reservoirs and achieve functional cures. Conventional approaches targeting Tat are limited by compensatory viral evolution and poor bioavailability. Next-generation interventions will employ precision-engineered tools, such as AI-optimized small molecules blocking Tat-P-TEFb interfaces and CRISPR-dCas9/Tat chimeric systems, for locus-specific LTR silencing or reactivation (“block and lock” or “shock and kill”). Advanced delivery platforms, including brain-penetrant lipid nanoparticles (LNPs), enable the targeted delivery of Tat-editing mRNA or base editors to microglial reservoirs. Single-cell multiomics elucidates Tat-mediated clonal heterogeneity, identifying “switchable” subpopulations for timed interventions. By integrating systems-level Tat interactomics, epigenetic engineering, and spatiotemporally controlled delivery, this review proposes a roadmap to disrupt HIV-1 persistence by hijacking the Tat switch, ultimately bridging mechanistic insights to clinical applications.

Adeno-associated viruses (AAVs) have emerged as the most favored viral vectors in clinical trials due to their diverse tissue tropism, low integration, and stable gene expression. However, pre-existing neutralizing antibodies and immune responses hinder AAV re-administration and limit its long-term gene therapy. To overcome this, we engineered a biomimetic artificial enveloped AAV (AEV) inspired by natural enveloped viruses, designed to shield against neutralizing antibodies and antigen-presenting cells. In mice, AEVs demonstrated superior transduction efficiency and minimal immune activation compared with AAVs in primary and secondary injections, even in environments with pre-existing antibodies and immune organs. Furthermore, AEVs showed flexibility in its modification for targeting different cells, enabling the use of multiple strategies to precisely target specific cells. This enhanced versatility allowed modified AEVs to provide significant therapeutic benefits in murine models of hemophilia B and diffuse large B cell lymphoma, expressing human factor IX and producing chimeric antigen receptor (CAR)-T cells in vivo.

The emergence of SARS-CoV-2 variants has underscored the urgent need for innovative vaccine strategies that provide robust and enduring protection against diverse strains. Our study introduces the FP-HR5 nanoparticle vaccine, designed to target the highly conserved S2 subunit of the spike protein, including the fusion peptide (FP) and heptad repeats (HR1 and HR2), using a 24-mer Helicobacter pylori ferritin platform. Administered intranasally, the FP-HR5-NP vaccine elicits robust systemic and mucosal immune responses in vivo, generating high titers of FP- and HR5-specific IgG antibodies. Notably, intranasal immunization resulted in elevated levels of secretory IgA and IgG in bronchoalveolar lavage fluid (BALF) and stimulated T-cell immune responses, significantly increasing resident memory B cells (BRM) and resident memory T cells (TRM) in the lungs. In hACE2 transgenic mice, three doses of FP-HR5-NP conferred substantial protection against Delta and Omicron variant challenges, with undetectable viral RNA levels in the lungs and no pathological changes observed. Overall, the FP-HR5-NP vaccine triggers comprehensive humoral and cellular immune responses at the mucosa, providing broad defense against SARS-CoV-2 variants and positioning it as a promising candidate for a universal COVID-19 vaccine solution.

The persistence of latent HIV-1 reservoirs remains a critical barrier to functional curing AIDS, as current latency-reversing agents (LRAs) exhibit limited clinical efficacy. While RNA modifications like N⁶-methyladenosine (m⁶A) regulate viral replication, their role in maintaining HIV-1 latency is poorly defined. Here, we identify the RNA-binding protein RBM39 as a scaffold organizing an m⁶A-dependent silencing complex that enforces viral latency. Through proteomic and functional analyses, we demonstrate that RBM39 recruits the m⁶A reader YTHDC1 and the RNA helicase DDX5, forming a tripartite complex that accelerates Tat RNA decay and enforces viral quiescence. Genetic or pharmacological degradation of RBM39 (using the clinically explored molecular glue indisulam) potently reactivates latent HIV-1 in J-Lat cell models, primary CD4⁺ T cells from people living with HIV-1 (PLWH), and synergizes with established LRAs (Bryostatin-1, JQ-1, SAHA) to broadly activate proviral reservoirs. Our work reveals a previously unrecognized host pathway in which RBM39-organized RNA decay complexes silence HIV-1 through epitranscriptomic regulation of Tat. In addition to establishing RBM39 as a promising therapeutic target for addressing the limitations of current "shock and kill" strategies, our findings establish a novel mechanistic framework for m⁶A-dependent regulation of viral gene expression. This framework may serve as a valuable reference for investigating similar regulatory mechanisms in other latent viral infections or oncogenic processes where RNA methylation plays a pivotal role.

Back tuina massage and oral administration of astragalus are two methods used in traditional Chinese medicine (TCM) to improve immune function. The aim of this study is to analyze the effects of tuina and orally administered astragalus on immunosuppressed rabbits using proteomics technology. Additionally, we investigate the potential mechanism of action of astragalus components on immunosuppression using an integration of network pharmacology and molecular docking technology. The findings suggested that cyclophosphamide-induced immunosuppression is primarily mediated through signaling pathways that include complement and coagulation cascades and chemical carcinogenesis. Immunosuppression is modulated by tuina and the oral administration of astragalus through various proteins and signaling pathways. A network pharmacology analysis indicated that quercetin, trichothecene isoflavones, and kaempferol in astragalus exhibited immunomodulatory effects. Molecular docking validation demonstrated that 15 major targets showed strong binding affinities to their respective interacting active ingredients. This trial provides references for future studies on the immune-boosting properties of tuina and oral astragalus.

Maintaining innate immune homeostasis is critical for preventing infections and autoimmune diseases but effective interventions are lacking. Here we identified C864-C869-mediated intermolecular disulfide-linkage formation as a critical step for human RIG-I activation that can be bidirectionally regulated to control innate immune homeostasis. The viral-stimulated C864-C869 disulfide linkage mediates conjugation of an SDS-resistant RIG-I oligomer, which prevents RIG-I degradation by E3 ubiquitin-ligase MIB2 and is necessary for RIG-I to perform liquid-liquid phase separation to compartmentalize downstream signalsome, thereby stimulating type I interferon signalling. The corresponding C865S 'knock-in' caused an oligomerization defect and liquid-liquid phase separation in mouse RIG-I, which inhibited innate immunity, resulting in increased viral load and mortality in mice. Using unnatural amino acids to generate covalent C864-C869 linkage and the development of an interfering peptide to block C864-C869 residues, we bidirectionally regulated RIG-I activities in human diseases. These findings provide in-depth insights on mechanism of RIG-I activation, allowing for the development of methodologies that hold promising implications in clinics.

Dental caries is a widespread bacterial infectious disease that imposes a significant public health burden globally. The primary culprits in caries development are cariogenic bacteria, notably Streptococcus mutans (S. mutans), due to their robust biofilm-forming capabilities. To address this issue, a series of cationic pyridinium-substituted photosensitizers with aggregation-induced emission have been designed. All of these aggregation-induced emission luminogens (AIEgens) exhibit outstanding microbial visualization and photodynamic killing of S. mutans, thanks to their luminous fluorescence and efficient singlet oxygen generation ability. Notably, one of the membrane-anchored AIEgens (TDTPY) can inactivate planktic S. mutans and its biofilm without causing significant cytotoxicity. Importantly, application of TDTPY-mediated photodynamic treatment on in vivo rodent models has yielded commendable imaging results and effectively slowed down caries progression with assured biosafety. Unlike traditional single-mode anticaries materials, AIEgens integrate the dual functions of detecting and removing S. mutans and are expected to build a new caries management diagnosis and treatment platform. To the best of our knowledge, this is also the first report on the use of AIEgens for anticaries studies both in vitro and in vivo.

Viruses, as opportunistic intracellular parasites, hijack the cellular machinery of host cells to support their survival and propagation. Numerous viral proteins are subjected to host-mediated post-translational modifications. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is SUMOylated on the lysine 65 residue, which efficiently mediates SARS2-NP’s ability in homo-oligomerization, RNA association, liquid-liquid phase separation (LLPS). Thereby the innate antiviral immune response is suppressed robustly. These roles can be achieved through intermolecular association between SUMO conjugation and a newly identified SUMO-interacting motif in SARS2-NP. Importantly, the widespread SARS2-NP R203K mutation gains a novel site of SUMOylation which further increases SARS2-NP’s LLPS and immunosuppression. Notably, the SUMO E3 ligase TRIM28 is responsible for catalyzing SARS2-NP SUMOylation. An interfering peptide targeting the TRIM28 and SARS2-NP interaction was screened out to block SARS2-NP SUMOylation and LLPS, and consequently inhibit SARS-CoV-2 replication and rescue innate antiviral immunity. Collectively, these data support SARS2-NP SUMOylation is critical for SARS-CoV-2 virulence, and therefore provide a strategy to antagonize SARS-CoV-2.