Biology subjects

Jiang, D.

Publications and source records attributed to Jiang, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Brain state locks silent memories in a trained fly connectome

Complete connectomes now exist for insect nervous systems, but whether a fixed wiring diagram can learn, and what its memories consist of, is unknown. Here, we trained a spiking model of the whole male Drosophila central nervous system, 167,106 neurons with fixed wiring, to plan moves and to remember a visual cue. Spikes write the cue into neuronal adaptation, which holds it silently until the next input reads it out. Cells that hold the trace are enriched for transcripts of a calcium-activated potassium channel in fly cell atlases. The learned readout recalls the trace only in the brain state of learning: the same trace evokes a different response at another delay, and a disease-like loss of potassium current rewrites the trace and changes how it is read. Learning in the new state is spared. Memory failure can arise from a change of state rather than a loss of storage.

neuroscience↗

bioRxiv2026

Selection for extreme neck elongation in crown birds

Variation in segment number, length, and identity is a major axis of diversification in bilaterians, shaped by developmental novelty and constraint. The near-invariant neck vertebral (cervical) count of mammals is a classic example of such constraint, yet we find that mammals occupy an unexceptional region of amniote cervical morphospace. In contrast, crown birds evolved extraordinarily long-neck proportions through increases in both cervical number and length, a combination only approached by ecologically-distinct sauropods among other archosaurs. This condition is widespread among living birds but largely absent from flight-capable stem avialans, excluding flight as a sole driver. A model of developmental evolution of segmentation demonstrates that coordinated increases in segment number and length are a predictable response to selection for regional elongation when viable homeotic changes are accessible. Our findings show how developmental constraints shape evolutionary routes to extreme morphologies and suggest major transformations can arise in traits beyond those commonly perceived as defining a clade's specialization.

evolutionary biology↗

bioRxiv2026

Mycobacteriophage Adephagia gp48 inhibits essential host cell wall biosynthesis enzyme mannose-1-phosphate guanylyltransferase

It is common for bacteriophages to encode proteins that are strongly inhibitory to growth of the bacterial host, and about 10% of mycobacteriophage-encoded proteins have this property. Adephagia is a Cluster K1 mycobacteriophage and prior cloning and expression of 66 Adephagia non-structural genes identified 14 that are toxic when expressed in Mycobacterium smegmatis. One of the expressed proteins, the 70-residue gp48, is highly toxic when expressed in both M. smegmatis and Mycobacterium abscessus and acts by binding to and inactivating the function of Msmeg_1828, a mannose-1-phosphate guanylyltransferase (Mpg). Mpg is an essential enzyme for biosynthesis of GDP-mannose, a precursor of several key cell wall constituents including lipoarabinomannan and phosphatidylinositol mannosides. The crystal structure of Adephagia gp48 shows that the N-terminal 43 residues form two alpha helices that strongly promote dimer formation; the C-terminal 27 residues are disordered but are predicted to bind Fe-S clusters via cysteine and histidine residues. Adephagia gp48 inhibits Mpg guanylyltransferase activity in vitro and is predicted to interrupt Mpg dimer formation. The C-terminal metal binding activity of gp48 is not required for toxicity, and non-toxic mutants have substitutions in the N-terminal alpha helices that are involved in dimerization. The selective advantage of Mpg inactivation for the phage is unclear, but it may protect from competing phages that require GDP-mannose derived molecules for efficient infection.

microbiology↗

bioRxiv2026

CD4+ T-Cells Drive Triple Negative Breast Cancer Recurrence via Non-Canonical TGFβ Signaling

Radiation therapy is a cornerstone of breast cancer treatment and reduces recurrence overall. However, patients with triple negative breast cancer (TNBC) continue to experience recurrence at higher rates than patients with other subtypes, especially when immunocompromised. While CD8 T-cells are known to mitigate recurrence, the role of CD4+ T-cell subsets in shaping the irradiated microenvironment remains unclear. We show that irradiated mammary tissue from mice accumulates CD4+ T-cells and exhibits a TGF{beta}-enriched cytokine milieu coincident with macrophage infiltration. We demonstrate that Th2-polarized CD4+ T-cells promote invasion of TNBC cells and macrophages through secretion of TGF{beta}. Neutralization of TGF{beta} significantly reduces this invasive phenotype. Mechanistically, Th2-conditioned media induces Tgfb1 expression in both TNBC cells and macrophages, establishing a TGF{beta}-dependent feed-forward amplification loop. In TNBC cells, Th2-derived TGF{beta} activates non-canonical signaling characterized by increased p38 MAPK and NF-{kappa}B phosphorylation, linking cytokine exposure to pro-invasive behavior. Together, these findings identify Th2-derived TGF{beta} as a driver of pro-invasive tumor reprogramming and suggest that interruption of Th2-TGF{beta} signaling may prevent recurrence following therapy.

cancer biology↗

bioRxiv2026

Extracellular vesicles drive cross-genus mycovirus transmission and suppress two fungal diseases

Mycoviruses are typically transmitted vertically through fungal reproduction or horizontally via hyphal anastomosis, but identical viruses in phylogenetically divergent fungi hint at unknown inter-species transmission mechanisms. Here, we identify fungal extracellular vesicles (EVs) as mediators of cross-genus mycovirus transmission. Using the hypovirulent Botrytis cinerea strain IBc-374 (harboring 16 mycoviruses) as a donor, we show that up to 13 mycoviruses are horizontally transmitted to Sclerotinia sclerotiorum during dual culture or plant co-inoculation, even though these two fungi belong to different genera and are generally considered incapable of hyphal anastomosis. Electron microscopy reveals abundant vesicle structures in IBc-374 hyphae, and nanoparticle tracking analysis showed that the strain secretes >11-fold more EVs than a virus-free strain. RT-PCR detects genomic RNAs of 7 mycoviruses in purified EVs, and the full-length viral genome in EVs was further validated with BcHV5 as example by fluorescence in situ hybridization and RT-PCR. Incubation of protoplast-derived germlings of S. sclerotiorum or B. cinerea with IBc-374 EVs leads to infection by 4-6 donor mycoviruses, demonstrating EV-mediated cross-genus transmission. Injection of mycovirus-carrying EVs into tobacco leaves followed by fungal inoculation also transmits two hypoviruses to both species. Application of IBc-374 hyphal fragment suspension significantly reduces lesion sizes caused by both pathogens on plants, and rescued two pathogens carrying multiple mycoviruses exhibit hypovirulence and impaired growth. Our findings reveal EVs as a cell-free vector that bypasses vegetative incompatibility, providing a mechanistic basis for cross-species viral spread and opening avenues for EV-based virus cocktails to control multiple fungal diseases. IN BRIEFWu et al. discover that fungal extracellular vesicles (EVs) can package and transmit multiple mycoviruses across genera from Botrytis cinerea to Sclerotinia sclerotiorum. EV-mediated delivery overcomes vegetative incompatibility barriers and reduces disease caused by both fungal pathogens, offering a cell-free strategy for mycovirus-based biological control.

microbiology↗

bioRxiv2026

Integrated Bioinformatics Analysis Reveals Candidate Hub Genes and Regulatory Networks Associated with Preeclampsia

Preeclampsia (PE) is a severe pregnancy-associated hypertensive disorder and a major contributor to maternal and perinatal morbidity and mortality. The mechanisms of PE pathogenesis are not yet understood. This paper aims to explore candidate PE-associated biomarkers and regulatory mechanisms using bioinformatics analysis of placental transcriptomic datasets. We downloaded placental transcriptomic datasetsGSE203507 and GSE148241 from GEO and investigated differentially expressed genes(DEGs) between PE and control samples. We performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO), and protein-protein interaction (PPI) analyses to characterize the potential role, disease associations, and interaction networks of the DEGs. We validated the mRNA expression patterns of candidate hub genes using two independent placental transcriptomic datasets, GSE143966 and GSE114691.We identified 263 DEGs in the discovery analysis and further obtained 150 overlapping DEGs including80 upregulated genes and 70 downregulated genes, for downstream analysis. We then identified eight candidate hub genes: OPRK1, OXGR1, HCAR3, CCR5, HCAR2, CXCL1, FPR3, and SSTR1using Meta scape software(v3.5.20260201). In the validation phase, most candidate hub genes showed broadly consistent mRNA expression trends across GSE114691 and GSE143966, while FPR3 showed weaker cross-dataset consistency. These findings provide candidate PE-associated genes and regulatory pathways for further experimental and clinical validation..

bioengineering↗

bioRxiv2026

Concurrent Stereotactic Body Radiation Therapy and KRAS Inhibition Synergistically Improve Pre-clinical Pancreatic Cancer Treatment

Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging cancers to treat due to the dismal survival rate, poor post-treatment outcome and profound resistance to a wide range of therapies. With mutant KRAS being a key driver, small molecule inhibitors targeting KRAS or pan-RAS (KRASi) have demonstrated exciting preclinical and early clinical anti-tumor efficacy, and the pan-RAS(ON) inhibitor daraxonrasib (RMC-6236) recently achieved Phase 3 clinically meaningful improvements in patient survival compared to chemotherapy. But resistance to RAS/KRAS inhibitor inevitably develops, which limits and compromises the treatment outcome. In this study, we investigated the combination of stereotactic body radiation therapy (SBRT) and KRAS inhibition (MRTX1133 and daraxonrasib) in the treatment of preclinical PDAC models. We found that this combination strategy synergistically suppresses PDAC cell growth in vitro and enhances tumor control while minimizing local recurrence in orthotopically implanted KPC (LSL-KrasG12D/+;Trp53R172H/+;Pdx1-Cre) murine PDAC tumors in vivo. As radiation therapy (RT) induces ferroptosis in multiple cancer types and mutant KRAS promotes various anti-ferroptotic mechanisms, we tested the role of ferroptosis in promoting tumor-control efficacy. Intriguingly, the addition of a ferroptosis inhibitor, liproxstatin-1, to the combination therapy significantly abrogated the in vivo synergism between SBRT and KRAS inhibition, suggesting that treatment-induced ferroptosis at least partially drives the synergistic efficacy of this combination strategy. Our study indicates that this SBRT-KRASi combination has the potential to overcome treatment resistance and improve outcomes in PDAC patients. These data directly support the design of a planned multi-center Phase 2 clinical trial with this combination strategy in locally advanced PDAC.

cancer biology↗

bioRxiv2026

CSF glucosylsphingosine is a central readout of GCase impairment across genetic and sporadic Parkinson’s disease

Parkinsons disease (PD) risk converges on lysosomal biology, including reduced activity of glucocerebrosidase (GCase), encoded by GBA1. Glucosylsphingosine (GlcSph), a toxic deacylated glycosphingolipid and established target engagement biomarker in Gaucher disease, is difficult to quantify in cerebrospinal fluid (CSF) because of low abundance and isomeric interference. We optimized and qualified targeted LC-MS/MS assays for GlcSph in CSF and plasma and measured GlcSph and GCase activity (4-MU assay) in participants from the Parkinsons Progression Markers Initiative (PPMI), including GBA1 and LRRK2 mutation carriers with and without PD, sporadic PD, and healthy controls. Group level analyses showed higher levels of CSF and plasma GlcSph in GBA1 heterozygous variant carriers independent of disease status, [~]120% (p<0.0001) and [~]61% (p<0.0001), respectively, with CSF elevations reflecting allelic dosage and, to a lesser degree, variant severity. Notably, elevated CSF GlcSph was observed not only in carriers of pathogenic GBA1 mutations but also in individuals harboring common GBA1 risk variants. CSF GlcSph was also elevated by [~]30% in sporadic PD (p=0.002) and by [~]40% LRRK2 mutation carriers (p=0.0003), indicating shared central GCase pathway perturbation across PD subtypes. CSF and plasma GlcSph levels showed poor concordance across groups with the exception of the GBA-PD group, supporting the hypothesis that central and peripheral GCase pathway dysfunction arise through distinct biological mechanisms. Together, these findings establish CSF GlcSph as a sensitive biomarker of central GCase pathway impairment and may support its use as a pharmacodynamic and target engagement biomarker for therapeutics targeting GCase in PD. More broadly, CSF GlcSph may enable identification of biologically defined GCase-pathway dysfunction beyond genetically defined GBA1-associated PD, with potential implications for patient stratification in future disease-modifying trials.

Molecular Biology↗

bioRxiv2026

OCOO-T : A SIMPLE AND SCALABLE VIRTUAL CELL MODEL FOR TRANSCRIPTIONAL PERTURBATION RESPONSE PREDICTION

Predicting single-cell transcriptional responses to genetic, chemical and cytokine perturbations is a fundamental challenge in computational biology and AI Virtual Cell (AIVC) modeling, with direct implications for drug discovery and the elucidation of gene regulatory networks. Existing approaches often rely on auxiliary cell-state encoders, hierarchical variational autoencoders, dedicated Transformer encoder-decoder modules, or gene-interaction priors to compress high-dimensional expression profiles into latent representations. While effective, these designs increase architectural complexity and may limit scalability and generalizability. This paper introduces OCOO-T 1, a minimalist flow-matching-based AIVC model for transcriptional perturbation response prediction. OCOO-T utilizes a vanilla Transformer stack that operates directly on continuous gene expression profiles and formulates perturbation response prediction as a continuous-time denoising process. Perturbation embeddings, dosage information, and cell-line/cell-type specificity are integrated through adaptive layer normalization and in-context tokens. Comprehensive evaluations on Tahoe100M, Replogle, and PBMC benchmarks demonstrate that OCOO-T achieves state-of-the-art performance across diverse perturbations and cell types while effectively scaling to long transcriptional profiles through patching and depatching of cellular contexts. By leveraging the simplicity of Transformer-based denoising for single-cell omics, OCOO-T provides an effective and scalable framework for in-silico cellular simulation.

bioinformatics↗

bioRxiv2026

Hypothalamic MCH neurons links tau pathology to sleep disruption

Sleep disruption is an early and pervasive feature of Alzheimers disease (AD), yet the circuit mechanisms linking tau pathology to sleep-wake dysfunction remain unresolved. Here, we identify melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) as a critical node disrupted in tauopathy. Longitudinal EEG/EMG recordings in PS19 mice reveal progressive impairments in sleep architecture and homeostasis. Histological analyses revealed significant degeneration of both MCH neurons and the neighboring hypocretin (Hcrt) neuronal population in the LH at late stages of tauopathy. In vivo fiber photometry recordings demonstrated a selective functional impairment of MCH neurons, characterized by reduced activity during REM sleep, whereas Hcrt neuronal activity remained largely preserved. In addition, cell-autonomous expression of mutant tau in MCH neurons recapitulates sleep disruption, establishing a causal role. Despite tauopathy-induced neuronal loss and reduced endogenous activity, optogenetic and chemogenetic activation show that MCH neurons retain functional capacity, and their activation restores sleep in aged PS19 mice. Together, these findings define a circuit mechanism linking tau pathology to sleep and identify MCH neurons as a tractable therapeutic target.

neuroscience↗

bioRxiv2026

Fibrotic lung-derived sphingosine-1-phosphate drives emotion-like disorders by regulating hippocampal neuroinflammation and cell death

The incidence of emotional disorders in patients with idiopathic pulmonary fibrosis (IPF) is substantially higher than that in the general population, severely compromising their quality of life. However, the underlying mechanisms remain poorly understood. In this study with multi-omics, we demonstrated that sphingosine-1-phosphate (S1P) derived from IPF lungs drive anxiety and depressive-like behaviors. Mechanistically, circulating S1P in the blood bound to hippocampal S1PR1 to regulate the PI3K/PKA/CREB signaling pathway, leading to synapse damage, the activation of microglia and astrocytes, neuroinflammation and ferroptosis in the hippocampus. Pharmacological inhibition of Sphk1, a key enzyme in S1P synthesis, reduced serum S1P levels and alleviated IPF-induced anxiety and depressive-like behaviors. Similarly, selective inhibition of hippocampal S1P receptor signaling using Fingolimod also attenuated neuroinflammation and ferroptosis and ameliorated mood disorders in IPF models. Collectively, these findings demonstrate that metabolite S1P from fibrotic lungs serves as a mediator of lung-to-brain functional influence, providing new insights into the IPF comorbid mood disorders and potential therapeutic targets.

neuroscience↗

bioRxiv2026

Curvature-mediated prewetting organize mitochondrial nucleoid

The emergence of spatiotemporal order in diffusive cellular environments requires physical mechanisms to overcome the entropic drive toward disorder. While the organizing role of chemical signaling is well characterized, how complex membrane curvature regulate soluble molecular organization remains a fundamental open question. Here, we establish membrane curvature as a thermodynamic control parameter for the condensation of soluble proteins through prewetting. Using the mitochondrial transcription factor TFAM, we demonstrate that intrinsic membrane curvature locally drives a prewetting transitiona surface-mediated phase separation distinct from bulk condensation. By combining in vitro reconstitution, live-cell super-resolution imaging, cryo-electron tomography, and thermodynamic theory, we show that negatively high-curvature regions lower the nucleation energy barrier of Tfam, driving localized protein condensation at physiological concentrations. These results reveal that membrane curvature does not merely scaffold cellular machinery but manipulates the local free energy landscape, establishing a geometric principle for the spatial control of biological processes.

biophysics↗

bioRxiv2026

Non-invasive MRI mapping of tissue-CSF water exchange reveals glymphatic fluid movement in live human cortex

Efficient metabolic waste clearance, via the postulated glymphatic system, is essential for neural homeostasis. However, direct visualization of tissue-cerebrospinal fluid (CSF) exchange remains limited, leading to ongoing debate in the neuroscientific field. The present work revealed evidence of tissue-CSF water exchange in the live human cortex, by employing a novel MRI technique demonstrating the flux of water molecules across the perivascular interface. We observed robust water exchange inside the cortical ribbon, which was more prominent than white matter and deep brain tissue. We validated that the signal originates from CSF and is independent of cerebral perfusion. Water exchange between tissue and CSF declined with age. Furthermore, we demonstrated for the first time that tissue-CSF exchange was impaired in Alzheimers disease (AD), in particular in regions where the perivascular space is clogged by anti-amyloid immunotherapy.

bioengineering↗

bioRxiv2026

Syndecan-1 Promotes Alveolar Type 2 Epithelial Cell Senescence during Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive, and fatal interstitial lung disease for which effective therapies remain limited. Alveolar type 2 (AT2) epithelial cells serve as facultative stem cells essential for alveolar repair; however, AT2 cell senescence disrupts epithelial regeneration and contributes to fibrotic remodeling in IPF. Syndecan-1 is a transmembrane heparan sulfate proteoglycan predominantly expressed by lung epithelial cells, but its role in AT2 dysfunction during fibrosis is poorly defined. Here, we demonstrate that syndecan-1 is robustly upregulated in AT2 cells in IPF and other fibrotic lung diseases, as well as in murine bleomycin-induced lung fibrosis. Syndecan-1 expression was further enhanced with aging and associated with increased fibrotic burden in aged mice. Using integrated human transcriptomic analyses, mouse genetic models, and epithelial cell-based systems, we show that excess syndecan-1 promotes cell-autonomous epithelial senescence and impairs AT2 progenitor function. Elevated syndecan-1 reduced AT2 renewal capacity, disrupted differentiation, and diminished surfactant protein C level, whereas genetic loss of syndecan-1 attenuated senescence and preserved epithelial function following injury. Together, these findings identify syndecan-1 as a critical epithelial regulator of AT2 senescence and maladaptive repair in pulmonary fibrosis and support targeting syndecan-1-driven epithelial dysfunction as a potential therapeutic strategy.

cell biology↗

bioRxiv2026

Immortalized AT2 Cell Lines from Healthy and IPF Lungs Enable 2D and 3D Cultures

Idiopathic pulmonary fibrosis (IPF) is characterized by impaired alveolar type 2 cell regeneration. However, robust in vitro models of human distal lung epithelium are limited. In this study, we generated immortalized AT2 cell lines from healthy and IPF lungs using HTII-280 sorting and SV40 large T antigen transduction. These lines retain key features of alveolar epithelial biology in both 2D and 3D cultures, including self-renewal, differentiation, and transitional cell states. They form 3D organoids efficiently under optimized feeder-free, serum-free medium conditions, with higher colony-forming capacity in healthy AT2 cell lines comparing with IPF AT2 cell lines. These accessible models recapitulate alveolar epithelial biology, offering a platform for cell-biology research and therapeutic development in lung diseases.

cell biology↗

bioRxiv2026

Spiral-on-a-Curve: wireless photoacoustic neuromodulation patch

Focused ultrasound neuromodulation offers a promising noninvasive strategy for precise deep-brain stimulation, yet conventional piezoelectric phased arrays rely on bulky hardware, high-voltage electronics, and complex phase control, limiting their scalability and wearable integration. Photoacoustic approaches enable wireless ultrasound generation but remain constrained by a trade-off between focusing precision, penetration depth, and robustness to optical misalignment. Here, we present a geometrically encoded passive photoacoustic patch (PPP) based on a spherical double logarithmic spiral (SDLS) array that achieves intrinsically stable and programmable acoustic focusing without electronic phase modulation. By distributing hemispherical CNT/PDMS photoacoustic emitters quasi-uniformly over an equal-path spherical surface and orienting each emitter toward a predefined focal point, the device establishes geometry-dominated wavefront convergence. Numerical simulations demonstrate that curved geometry is a prerequisite for phase-free focusing, while the nonperiodic spiral topology suppresses sidelobes and mitigates interference artifacts Compared with continuous spherical or periodic concentric arrays, the SDLS architecture exhibits substantially enhanced robustness to optical axis displacement, reducing focal tilt from > 14{degrees} to approximately 5{degrees} under 2 mm lateral misalignment. Experimental three-dimensional hydrophone mapping confirms millimeter-scale focusing at approximately 7 mm depth with a full width at half-maximum of 1.3 mm and peak pressures up to 8 MPa under safe laser exposure ([≤] 20 mJ/cm2). The focal region can be continuously tuned by adjusting illumination aperture size without altering device geometry or excitation schemes. The patch demonstrates excellent thermal and acoustic stability during prolonged operation and enables region-specific motor cortex stimulation in vivo, eliciting distinct electromyographic responses in forelimb and hindlimb muscles. By shifting ultrasound beam formation from electronic phase control to intrinsic three-dimensional geometry, this work establishes a lightweight, wire-free, and optically programmable platform for robust wearable neuromodulation and scalable bioacoustic interfaces.

bioengineering↗

bioRxiv2026

Phenotypic complexity determines the predictability of molecular convergence

Whether the outcomes of evolution are predictable remains a central question in evolutionary biology. Convergent evolution, in which similar phenotypes arise independently in distinct lineages, is often interpreted as evidence of predictability under shared selective pressures. However, empirical studies have shown that convergent phenotypes can exhibit similar or disparate molecular bases, and no general frame-work predicts when convergence should occur. Here, we show that phenotypic complexity determines the extent of convergence under shared conditions. Using a deliberately minimal abstraction linking genotype and phenotype and evolutionary simulations, we investigated how regulatory gene expression programs evolve under selection for shared phenotypic optima. We find that phenotypes of low complexity can be produced by diverse regulator expression programs, permitting phenotypic convergence despite molecular divergence. However, as the complexity of the target phenotype increases, the variety of viable regulatory solutions decreases, funneling independently evolving lineages towards similar expression programs. In this regime, molecular convergence emerges as a predictable consequence of selection acting on finite regulatory repertoires, consistent with the phenomenon of "deep homology" observed in structures like eyes and limbs. Allowing evolutionary changes in regulator-target interactions relaxes these constraints and enhances divergence in expression between phenotypically convergent species. Together, our results provide general expectations for predicting when phenotypic convergence should be accompanied by convergent genetic mechanisms, and shed light on the causes of convergence in a broad range of phenotypic traits.

evolutionary biology↗

bioRxiv2025

Synchronized Latency Reversal and Immune Clearance by a Multifunctional Fusion Protein Enables HIV-1 Reservoir Reduction

Strategies that concurrently reactivate latent reservoirs and enhance immune-mediated clearance hold significant promise for achieving an HIV cure. Here, we developed hyperIL-15xsCD4-Fc (15xsCD4-Fc), a fusion protein that integrates latency reactivation, targeted immune engagement, and effector-mediated killing into a single molecule. This agent not only potently reverses HIV-1 latency in CD4+ T cells from people living with HIV-1 (PLWH) through coordinated IL-15 receptor signaling and sCD4-mediated HIV-1 envelope (Env) engagement, but also enhances antigen-specific CD8+ T cell response in PBMCs derived from PLWH. Furthermore, 15xsCD4-Fc enables Env-specific elimination of reactivated latently infected cells by NK cells while preventing off-target cytotoxicity. In PBMCs from PLWH, 15xsCD4-Fc reduced replication-competent HIV-1 DNA by 93.8%. In antiretroviral treated HIV-1-infected humanized mice, the molecule demonstrated both safety and efficacy in diminishing viral reservoir in lymphoid organs. This spatiotemporally coupled approach to reservoir exposure and immune recognition establishes a clinically viable strategy for clearing the HIV-1 reservoir. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/693434v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@8f8f0org.highwire.dtl.DTLVardef@10f63f7org.highwire.dtl.DTLVardef@16c1de2org.highwire.dtl.DTLVardef@11e1787_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗