Biology subjects

Chen, C.

Publications and source records attributed to Chen, C..

At least 397 records · Page 22Linked to original sources

bioRxiv2023

Juvenile niches select between two distinct development trajectories and symbiosis modes in vent shrimps

Most animal species have a singular developmental pathway and adult ecology, but developmental plasticity is well-known in some like honeybees where castes display profoundly different morphology and ecology. An intriguing case is the Atlantic deep-sea hydrothermal vent shrimp Rimicaris hybisae/chacei that share dominant COI haplotypes but develops into either the symbiont-reliant hybisae with a hypertrophied head chamber (in the Mid-Cayman Spreading Centre) or the mixotrophic chacei with a narrow head chamber (on the Mid-Atlantic Ridge). Here, we use X-ray micro-computed tomography and fluorescent in situ hybridization to show that key anatomical shifts in both occur between the juvenile-subadult transition, when those developing into hybisae have fully established symbiosis but not chacei. On the Mid-Atlantic Ridge the diet of R. chacei has been hypothetically linked to competition with the obligatorily symbiotic congener R. exoculata, and we find anatomical evidences that R. exoculata is indeed better adapted for symbiosis - suggesting the chacei morph could be an adaptation to prevent competitive exclusion. Our results suggest that the two distinct development trajectories are likely selected according to the diet available to the juveniles, determined by whether energetically sufficient symbiont colonisation has occurred before reaching subadult stage.

evolutionary biology↗

bioRxiv2023

Activity-Induced MeCP2 Phosphorylation Regulates Retinogeniculate Synapse Refinement

Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelopmental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MeCP2 causes miswiring of neural circuits due to defects in the brains capacity to respond to changes in neuronal activity and sensory experience. Here we show that MeCP2 is phosphorylated at four residues in the brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from that previously reported for Mecp2 null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period. SIGNIFICANCE STATEMENTRett syndrome (RTT) is an X-linked neurodevelopmental disorder that predominantly affects girls. RTT is caused by loss of function mutations in a single gene MeCP2. Girls with RTT develop normally during their first year of life, but then experience neurological abnormalities including breathing and movement difficulties, loss of speech, and seizures. This study investigates the function of the MeCP2 protein in the brain, and how MeCP2 activity is modulated by sensory experience in early life. Evidence is presented that sensory experience affects MeCP2 function, and that this is required for synaptic pruning in the brain. These findings provide insight into MeCP2 function, and clues as to what goes awry in the brain when the function of MeCP2 is disrupted.

neuroscience↗

bioRxiv2023

BRD4 directs mitotic cell division by inhibiting DNA damage

BRD4 binds to acetylated histones to regulate transcription and drive cancer cell proliferation. However, the role of BRD4 in normal cell growth remains to be elucidated. Here we investigated the question by using mouse embryonic fibroblasts with conditional Brd4 knockout (KO). We found that Brd4KO cells grow more slowly than wild type cells: they do not complete replication, fail to achieve mitosis, and exhibit extensive DNA damage throughout all cell cycle stages. BRD4 was required for expression of more than 450 cell cycle genes including genes encoding core histones and centromere/kinetochore proteins that are critical for genome replication and chromosomal segregation. Moreover, we show that many genes controlling R-loop formation and DNA damage response (DDR) require BRD4 for expression. Finally, BRD4 constitutively occupied genes controlling R-loop, DDR and cell cycle progression. We suggest that BRD4 epigenetically marks those genes and serves as a master regulator of normal cell growth.

cell biology↗

bioRxiv2023

Identification and Characterization of CtUGT3 as the Key Player of Astragalin Biosynthesis in Safflower

Safflower (Carthamus tinctorius L.) flowers are used as a traditional Chinese medicine for a long history. Flavonoids are the main bioactive components in safflower flowers, and most of them exist in the form of flavonoid glycosides. Only few glycosyltransferases have been identified in safflower. To reveal the uridine diphosphate glycosyltransferase (UGT) involved in flavonoid glycosides biosynthesis in safflower, a metabolomics and transcriptome analysis was performed by using the flowers under different light qualities treatments. Three differentially expressed UGT genes were screened, and their expressions were significantly related with concentrations of 9 flavonoid O-glycosides. Safflower corolla protoplasts were further used to confirm flavonoid O-glycosylation ability of UGT candidates. The astragalin (kaempferol 3-O-glucoside) content was only significantly increased when CtUGT3 was overexpressed in protoplasts. The biochemical properties and kinetic parameters of CtUGT3 were determined. CtUGT3 also showed flavonoid 3-OH and 7-OH glycosylation activities in vitro. Molecular modeling and site-directed mutagenesis revealed that E384 and S276 were critical catalytic residues for the 3-OH glycosylation of CtUGT3. These results demonstrate that CtUGT3 has a flavonoid 3-OH glycosylation function and is involved in the biosynthesis of astragalin in safflower. This study provides insights into the catalytic mechanisms of flavonoid O-glycosyltransferases, and makes a reference for flavonoid biosynthesis genes research in medicinal plants.

plant biology↗

bioRxiv2023

An uncanonical CDK6 activity inhibits cilia function by suppressing axoneme polyglutamylation

Tubulin polyglutamylation is a post-translational modification that occurs primarily along the axoneme of cilia. Defective axoneme polyglutamylation impairs cilia function and has been correlated with ciliopathies, including Joubert Syndrome (JBTS). However, the precise mechanisms regulating proper axoneme polyglutamylation remain vague. Here, we show that Cyclin-Dependent Kinase 6 (CDK6), but not its paralog CDK4, localizes to cilia base and suppresses axoneme polyglutamylation by phosphorylating RAB11-interacting protein FIP5 at site S641, a critical regulator of cilia import of glutamylases. S641 phosphorylation disrupts the ciliary recruitment of FIP5 by impairing its association with RAB11, thereby reducing the ciliary import of glutamylases. Interestingly, significant upregulation of CDK6 and defective axoneme polyglutamylation were observed in Autosomal dominant polycystic kidney disease (ADPKD) cells. Encouragingly, the FDA-approved CDK4/6 inhibitor Abemaciclib can effectively restore cilia function in JBTS and ADPKD cells with defective glutamylation and suppresses renal cystogenesis in an ex vivo ADPKD model. In summary, our study elucidates regulatory mechanisms governing axoneme polyglutamylation and suggests developing CDK6-specific inhibitors could be a promising therapeutic strategy to enhance cilia function in ciliopathy patients.

cell biology↗

bioRxiv2023

NG2 Glia Reprogramming Induces Robust Axonal Regeneration After Spinal Cord Injury

Spinal cord injury (SCI) often leads to neuronal loss, axonal degeneration and behavioral dysfunction. We recently show that in vivo reprogramming of NG2 glia produces new neurons, reduces glial scaring, and ultimately leads to improved function after SCI. By examining endogenous neurons, we here unexpectedly uncover that NG2 glia reprogramming also induces robust axonal regeneration of the corticospinal tract and serotonergic neurons. Such reprogramming-induced axonal regeneration may contribute to the reconstruction of neural networks essential for behavioral recovery.

neuroscience↗

bioRxiv2023

NRF2 activators inhibit influenza A virus replication by interfering with nucleo-cytoplasmic export of viral RNPs in an NRF2-independent manner

In addition to antioxidative and anti-inflammatory properties, activators of the cytoprotective nuclear factor erythroid-2-like-2 (NRF2) signaling pathway have antiviral effects, but the underlying antiviral mechanisms are incompletely understood. We evaluated the ability of the NRF2 activators 4-octyl itaconate (4OI), bardoxolone methyl (BARD), sulforaphane (SFN), and the inhibitor of exportin-1 (XPO1)-mediated nuclear export selinexor (SEL) to interfere with influenza virus A/Puerto Rico/8/1934 (H1N1) infection of human cells. All compounds reduced viral titers in supernatants from A549 cells and vascular endothelial cells in the order of efficacy SEL>4OI>BARD=SFN, which correlated with their ability to prevent nucleo-cytoplasmic export of viral nucleoprotein and the host cell protein p53. In contrast, intracellular levels of viral HA mRNA and nucleocapsid protein (NP) were unaffected. Knocking down mRNA encoding KEAP1 (the main inhibitor of NRF2) or inactivating the NFE2L2 gene (which encodes NRF2) revealed that physiologic NRF2 signaling restricts IAV replication. However, the antiviral effect of all compounds was NRF2-independent. Instead, XPO1 knock-down greatly reduced viral titers, and incubation of Calu3 cells with an alkynated 4OI probe demonstrated formation of a covalent complex with XPO1. Ligand-target modelling predicted covalent binding of all three NRF2 activators and SEL to the active site of XPO1 involving the critical Cys528. SEL and 4OI manifested the highest binding energies, whereby the 4-octyl tail of 4OI interacted extensively with the hydrophobic groove of XPO1, which binds nuclear export sequences on cargo proteins. Conversely, SEL as well as the three NRF2 activators were predicted to covalently bind the functionally critical Cys151 in KEAP1. Blocking XPO1-mediated nuclear export may, thus, constitute a "noncanonical" mechanism of anti-influenza activity of electrophilic NRF2 activators that can interact with similar cysteine environments at the active sites of XPO1 and KEAP1. Considering the importance of XPO1 function to a variety of pathogenic viruses, compounds that are optimized to inhibit both targets may constitute an important class of broadly active host-directed treatments that embody anti-inflammatory, cytoprotective, and antiviral properties. Author summaryVirus infections often cause organ damage via excessive inflammation and oxidative stress. The identification of host-directed treatments that reduce inflammation, accumulation of reactive oxygen species, and viral infectivity is an important goal of antiviral drug development. One advantage of host-directed antivirals is that their targets are encoded by the stable host genome, making emergence of viral resistance less likely. The KEAP1/NRF2 signaling pathway is the most important pathway in humans that protects cells from oxidative stress, and it also induces antiviral and anti-inflammatory responses. NRF2 activators, therefore, are promising candidates for development of host-directed antivirals. We evaluated three NRF2-activating compounds as host-directed treatments for influenza A virus (IAV) infection. All three compounds reduced viral replication, cellular inflammation, and reactive oxygen species. Surprisingly, these effects were completely independent of NRF2 signaling. Instead, we found that these compounds (particularly 4-octyl itaconate) interfere with export of viral RNA/protein complexes from the nucleus, thereby reducing release of viral particles. The most plausible explanation is that the "natural" target of these compounds, KEAP1 (which limits NRF2 signaling), and the nuclear export factor XPO1 (which is required for egress of IAV from the nucleus) contain similar binding sites, thus allowing "NRF2 activators" to also inhibit XPO1.

microbiology↗

bioRxiv2023

The impact of common variants on gene expression in the human brain: from RNA to protein to schizophrenia risk

BackgroundThe impact of genetic variants on gene expression has been intensely studied at the transcription level, yielding invaluable insights into the association between genes and the risk of complex disorders, such as schizophrenia (SCZ). However, the downstream impact of these variants and the molecular mechanisms connecting transcription variation to disease risk are not well understood. ResultsWe quantitated ribosome occupancy in prefrontal cortex samples of the BrainGVEX cohort. Together with transcriptomics and proteomics data from the same cohort, we performed cis-Quantitative Trait Locus (QTL) mapping and identified, at 10% false discovery rate, 3,253 expression QTLs (eQTLs), 1,344 ribosome occupancy QTLs (rQTLs), and 657 protein QTLs (pQTLs) out of 7,458 genes from 185 samples. Of the eQTLs identified, only 34% have their effects propagated to the protein level. Further analysis on the effect size of prefrontal cortex eQTLs identified from an independent dataset clearly replicated the post-transcriptional attenuation of eQTL effects. We identified omics-specific QTLs and investigated their potential in driving disease risks. Using both a variant-based approach and a gene-based approach, we identified genes containing expression-specific QTLs (esQTLs), ribosome-occupancy-specific QTLs (rsQTLs), and protein-specific QTLs (psQTLs). Among the variant-based omics-specific QTL, 38 showed strong colocalization with brain associated disorder GWAS signals, 29 of them are esQTLs. From the gene-based approach, we found 11 brain associated disorder risk genes that are driven predominantly by omics-specific QTL, all of them are driven by variants impacting transcriptional regulation. To take a complementary approach to further investigate the functional relevance of genes driven predominantly by attenuated eQTL signals, we identified SCZ risk genes using each omics independently and then investigated the omics-specificity of the driver regulatory process for each risk gene. Using S-PrediXcan we identified 74 SCZ risk genes across the three omics, 30% of which were novel, and 67% of these risk genes were confirmed to be causal in a MR-Egger test. Notably, 52 out of the 74 risk genes were identified using eQTL data and 68% of these SCZ-risk-gene-driving eQTLs show little to no evidence of driving corresponding variations at the protein level. ConclusionThe effect of eQTLs on gene expression in the prefrontal cortex is commonly attenuated post-transcriptionally. Many of the attenuated eQTLs still correlate with GWAS signals of brain associated complex disorders, indicating the possibility that these eQTL variants drive disease risk through mechanisms other than regulating protein expression level. Further investigation is needed to elucidate the mechanistic link between attenuated eQTLs and brain associated complex disorders.

genetics↗

bioRxiv2023

Transcranial stimulation of alpha oscillations modulates brain state dynamics in sustained attention

The brain operates an advanced complex system to support mental activities. Cognition is thought to emerge from dynamic states of the complex brain system, which are organized spatially through large- scale neural networks and temporally via neural synchrony. However, specific mechanisms underlying these processes remain obscure. Applying high-definition alpha-frequency transcranial alternating-current stimulation (HD -tACS) in a continuous performance task (CPT) during functional resonance imaging (fMRI), we causally elucidate these major organizational architectures in a key cognitive operation-- sustained attention. We demonstrated that -tACS enhanced both electroencephalogram (EEG) alpha power and sustained attention, in a correlated fashion. Akin to temporal fluctuations inherent in sustained attention, our hidden Markov modeling (HMM) of fMRI timeseries uncovered several recurrent, dynamic brain states, which were organized through a few major neural networks and regulated by the alpha oscillation. Specifically, during sustain attention, -tACS regulated the temporal dynamics of the brain states by suppressing a Task-Negative state (characterized by activation of the default mode network/DMN) and Distraction state (with activation of the ventral attention and visual networks). These findings thus linked dynamic states of major neural networks and alpha oscillations, providing important insights into systems-level mechanisms of attention. They also highlight the efficacy of non-invasive oscillatory neuromodulation in probing the functioning of the complex brain system and encourage future clinical applications to improve neural systems health and cognitive performance.

neuroscience↗

bioRxiv2023

Shortcut barcoding and early pooling for scalable multiplex single-cell reduced-representation CpG methylation sequencing at single nucleotide resolution

DNA methylation is essential for a wide variety of biological processes, yet the development of a highly efficient and robust technology remains a challenge for routine single-cell analysis. We developed a multiplex scalable single-cell reduced representation bisulfite sequencing (msRRBS) technology with off-the-shelf reagents and equipment. It allows cell-specific barcoded DNA fragments of individual cells to be pooled before bisulfite conversion, free of enzymatic modification or physical capture of the DNA ends, and achieves unparalleled read mapping rates of 62.51%, covering 59.95% of CpG islands and 71.62% of promoters in K562 cells on average. Its reproducibility is shown in duplicates of bulk cells with near perfect correlation (R=0.97-99). At a low 1 Mb of clean reads, msRRBS provides consistent coverage of CpG islands and promoters, outperforming the conventional methods with orders of magnitude reduction in cost. Here, we use this method to characterize the distinct methylation patterns and cellular heterogeneity of 6 cell lines, and leukemia and hepatocellular carcinoma models. Taking 4 hours of hands-on time, msRRBS offers a unique, highly efficient approach for dissecting methylation heterogeneity in a variety of multicellular systems.

genomics↗

bioRxiv2023

The Secondary Somatosensory Cortex Gates Mechanical and Thermal Sensitivity

The cerebral cortex is vital for the perception and processing of sensory stimuli. In the somatosensory axis, information is received by two distinct regions, the primary (S1) and secondary (S2) somatosensory cortices. Top-down circuits stemming from S1 can modulate mechanical and cooling but not heat stimuli such that circuit inhibition causes blunted mechanical and cooling perception. Using optogenetics and chemogenetics, we find that in contrast to S1, an inhibition of S2 output increases mechanical and heat, but not cooling sensitivity. Combining 2-photon anatomical reconstruction with chemogenetic inhibition of specific S2 circuits, we discover that S2 projections to the secondary motor cortex (M2) govern mechanical and thermal sensitivity without affecting motor or cognitive function. This suggests that while S2, like S1, encodes specific sensory information, that S2 operates through quite distinct neural substrates to modulate responsiveness to particular somatosensory stimuli and that somatosensory cortical encoding occurs in a largely parallel fashion.

neuroscience↗

bioRxiv2023

Enhancing AlphaFold-Multimer-based Protein Complex Structure Prediction with MULTICOM in CASP15

AlphaFold-Multimer has emerged as the state-of-the-art tool for predicting the quaternary structure of protein complexes (assemblies or multimers) since its release in 2021. To further enhance the AlphaFold-Multimer-based complex structure prediction, we developed a new quaternary structure prediction system (MULTICOM) to improve the input fed to AlphaFold-Multimer and evaluate and refine the outputs generated by AlphaFold2-Multimer. Specifically, MULTICOM samples diverse multiple sequence alignments (MSAs) and templates for AlphaFold-Multimer to generate structural models by using both traditional sequence alignments and new Foldseek-based structure alignments, ranks structural models through multiple complementary metrics, and refines the structural models via a Foldseek structure alignment-based refinement method. The MULTICOM system with different implementations was blindly tested in the assembly structure prediction in the 15th Critical Assessment of Techniques for Protein Structure Prediction (CASP15) in 2022 as both server and human predictors. Our server (MULTICOM_qa) ranked 3rd among 26 CASP15 server predictors and our human predictor (MULTICOM_human) ranked 7th among 87 CASP15 server and human predictors. The average TM-score of the first models predicted by MULTICOM_qa for CASP15 assembly targets is [~]0.76, 5.3% higher than [~]0.72 of the standard AlphaFold-Multimer. The average TM-score of the best of top 5 models predicted by MULTICOM_qa is [~]0.80, about 8% higher than [~]0.74 of the standard AlphaFold-Multimer. Moreover, the novel Foldseek Structure Alignment-based Model Generation (FSAMG) method based on AlphaFold-Multimer outperforms the widely used sequence alignment-based model generation. The source code of MULTICOM is available at: https://github.com/BioinfoMachineLearning/MULTICOM3.

bioinformatics↗

bioRxiv2023

Pathological Tau transmission initiated by binding lymphocyte-activation gene 3

The spread of prion-like protein aggregates is believed to be a common driver of pathogenesis in many neurodegenerative diseases. Accumulated tangles of filamentous Tau protein are considered pathogenic lesions of Alzheimers disease (AD) and related Tauopathies, including progressive supranuclear palsy, and corticobasal degeneration. Tau pathologies in these illnesses exhibits a clear progressive and hierarchical spreading pattern that correlates with disease severity1, 2. Clinical observation combined with complementary experimental studies3, 4 have shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remains poorly understood. Here, we show that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF, but not monomer, of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. Our results identify neuronal Lag3 as a receptor of pathologic Tau in the brain, and for AD and related Tauopathies a therapeutic target. One Sentence SummaryLag3 is a neuronal receptor specific for Tau PFF, and is required for uptake, propagation and transmission of Tau pathology.

neuroscience↗

bioRxiv2023

Generalized fear following acute stress is caused by change in co-transmitter identity of serotonergic neurons

Overgeneralization of fear to harmless situations is a core feature of anxiety disorders resulting from acute stress, yet the mechanisms by which fear becomes generalized are poorly understood. Here we show that generalized fear in mice in response to footshock results from a transmitter switch from glutamate to GABA in serotonergic neurons of the lateral wings of the dorsal raphe. We observe a similar change in transmitter identity in the postmortem brains of PTSD patients. Overriding the transmitter switch in mice using viral tools prevents the acquisition of generalized fear. Corticosterone release and activation of glucocorticoid receptors trigger the switch, and prompt antidepressant treatment blocks the co-transmitter switch and generalized fear. Our results provide new understanding of the plasticity involved in fear generalization. One sentence summaryAcute stress produces generalized fear by causing serotonergic neurons to switch their co-transmitter from glutamate to GABA

neuroscience↗

bioRxiv2023

Connecting higher order interactions with ecological stability in experimental aquatic food webs

Community ecology is built on theories that represent the strength of interactions between species as pairwise links. Higher order interactions occur when the presence of a third (or more) species changes the pairwise interaction between a focal pair. Recent theoretical work has highlighted the stabilizing role of higher order interactions for large, simulated communities, yet it remains unclear how important higher order effects are in real communities. Here we used experimental communities of aquatic protists to examine the relationship between higher-order interactions and community stability (as measured by the persistence of species in a community). We cultured a focal pair of consumers in the presence of additional competitors and a predator and collected time series data of their abundances. We then fitted competition models with and without HOIs to measure interaction strength between the focal pair across different community compositions. We used survival analysis to measure the persistence of individual species. We found evidence that additional species positively affected persistence of the focal species and that HOIs were present in most of our communities. However, persistence was only linked to HOIs for one of the focal species. Our results vindicate community ecology theory positing that species interactions may deviate from assumptions of pairwise interactions, opening avenues to consider possible consequences for coexistence and community stability.

ecology↗

bioRxiv2023

The landscape of tolerated genetic variation in humans and primates

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole genome sequencing data for 809 individuals from 233 primate species, and identified 4.3 million common protein-altering variants with orthologs in human. We show that these variants can be inferred to have non-deleterious effects in human based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases. One Sentence SummaryDeep learning classifier trained on 4.3 million common primate missense variants predicts variant pathogenicity in humans.

genomics↗

bioRxiv2023

Syntheses of Pyrimidine-Modified Seleno-DNAs as Stable Antisense Molecules

Chemically modified antisense oligonucleotides (ASO) currently in pre-clinical and clinical experiments mainly focus on the 2-position derivatizations to enhance stability and targeting affinity. Considering the possible incompatibility of 2-modifications with RNase H stimulation and activity, we have hypothesized that the atom specific modifications on nucleobases can retain the complex structure and RNase H activity, while enhancing ASOs binding affinity, specificity, and stability against nucleases. Herein we report a novel strategy to explore our hypothesis by synthesizing the deoxynucleoside phosphoramidite building block with the seleno-modification at 5-position of thymidine, as well as its Se-oligonucleotides. Via X-ray crystal structural study, we found that the Se-modification was located in the major groove of nucleic acid duplex and didnt cause the thermal and structural perturbations. Surprisingly, our nucleobase-modified Se-DNAs were exceptionally resistant to nuclease digestion, while compatible with RNase H activity. This affords a novel avenue for potential antisense modification in the form of Se-antisense oli-gonucleotides (Se-ASO).

biochemistry↗

bioRxiv2023

SIV clearance from neonatal macaques following transient CCR5 depletion

SUMMARY PARAGRAPHTreatment of people with HIV (PWH) with antiretroviral therapy (ART) results in sustained suppression of viremia, but HIV persists indefinitely as integrated provirus in CD4-expressing cells. Intact persistent provirus, the "rebound competent viral reservoir" (RCVR), is the primary obstacle to achieving a cure. Most variants of HIV enter CD4+ T cells by binding to the chemokine receptor, CCR5. The RCVR has been successfully depleted only in a handful of PWH following cytotoxic chemotherapy and bone marrow transplantation from donors with a mutation in CCR5. Here we show that long-term SIV remission and apparent cure can be achieved for infant macaques via targeted depletion of potential reservoir cells that express CCR5. Neonatal rhesus macaques were infected with virulent SIVmac251, then treated with ART beginning one week after infection, followed by treatment with either a CCR5/CD3-bispecific or a CD4-specific antibody, both of which depleted target cells and increased the rate of plasma viremia decrease. Upon subsequent cessation of ART, three of seven animals treated with CCR5/CD3-bispecific antibody rebounded quickly and two rebounded 3 or 6 months later. Remarkably, the other two animals remained aviremic and efforts to detect replication-competent virus were unsuccessful. Our results show that bispecific antibody treatment can achieve meaningful SIV reservoir depletion and suggest that functional HIV cure might be achievable for recently infected individuals having a restricted reservoir.

immunology↗