Biology subjects

Ye, F.

Publications and source records attributed to Ye, F..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Antibacterial mechanism of inosine against Alicyclobacillus acidoterrestris

Inosine could potentially become a novel antibacterial agent against A. acidoterrestris as low-dose of inosine can prevent A. acidoterrestris contamination. However, until now the antibacterial mechanism of inosine targeting A. acidoterrestris is still unknown. In this study, to unravel the mechanism of inosine against A. acidoterrestris puzzle, the effects of inosine on bacterial surface hydrophobicity, intracellular protein content, cell membrane damage extent and permeability of the A. acidoterrestris were investigated. The results showed that inosine can effectively inhibit the growth and reproduction of A. acidoterrestris by destroying the integrity of cell membrane and increasing its permeability, causing the leakage of intracellular nutrients. Furthermore, the interaction networks of inosine target proteins were analyzed. The interaction networks further revealed that damage of bacterial cell membrane might be relevant to inosines effect on bacterial DNA replication and cell energy metabolism through regulating nucleotide synthesis and metabolism and the activity of translation initiation factors. Finally, the antibacterial mechanism of inosine against A. acidoterrestris was proposed.

microbiology↗

bioRxiv2023

Structural Basis of σ54 Displacement and Promoter Escape in Bacterial Transcription

Gene transcription is a fundamental cellular process carried out by RNA polymerase (RNAP). Transcription initiation is highly regulated and in bacteria, transcription initiation is mediated by {sigma} factors, which recruit RNA polymerase (RNAP) to the promoter DNA region and facilitate open complex formation, where double stranded DNA is opening up into a transcription bubble and template strand DNA is in position for initial RNA synthesis. During initial transcription, DNA downstream of the transcription start site is fed into the active site of RNAP, whilst the upstream promoter DNA remains tethered to the RNAP via the {sigma} factor, resulting in a build-up of tension. In order to progress to the processive elongation state, RNAP must escape from the promoter, and displace or dissociate the {sigma} factor. Bacteria s factors can be broadly separated into two classes with the majority belong to the s70 class, represented by the {sigma}70 that regulate housekeeping genes. {sigma}54 forms a class on its own and regulate stress response genes. Extensive studies on {sigma}70 have revealed the molecular mechanisms of {sigma}70 promoter escape while how {sigma}54 transitions from initial transcription to elongation is unknown. Here we present a series of cryo electron microscopy structures of the {sigma}54 factor with progressively longer RNA, revealing the molecular mechanism of {sigma}54 displacement and promoter escape. Our data show that the initial instability is driven by DNA scrunching, and the final displacement steps are driven by both RNA extension and DNA scrunching.

biophysics↗

bioRxiv2023

Cryo-EM structure of the human G-protein coupled receptor 1 (GPR1) - Gi protein complex bound to the chemerin C-terminal nonapeptide

Chemerin is an adipokine with chemotactic activity to a subset of leukocytes. Chemerin mainly acts through its C-terminal nonapeptide (YFPGQFAFS, C9) that bind to three G protein-coupled receptors including chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and C-C chemokine receptor-like 2 (CCRL2). We examined C9 signaling through GPR1 and found this receptor capable of Gi signaling but very weak {beta}-arrestin signaling. Here we report high-resolution cryo-EM structures of GPR1-Gi complexes bound to full-length chemerin and to C9, respectively. Unlike C9 that inserts directly into a transmembrane binding pocket, full-length chemerin uses its N-terminal globular core for extensive interaction with the N terminus of GPR1. Within the binding pocket, the C terminal loop containing the nonapeptide takes the same "S-shape" pose as synthetic C9 nonapeptide. These findings explain why the nonapeptide is a full agonist of GPR1, and demonstrate that chemerin uses a "two-site" model for interaction with GPR1. An analysis of the GPR1-Gi protein interface found high similarities to the CMKLR1-Gi complex, as confirmed by site-directed mutagenesis with functional verifications. Our structural analysis demonstrates shared features with chemokines in that chemerin acts as a "reverse chemokine" with switched functions of its N and C termini in the interaction with GPR1.

pharmacology and toxicology↗

bioRxiv2023

On Pre-trained Language Models for Antibody

AO_SCPLOWBSTRACTC_SCPLOWAntibodies are vital proteins offering robust protection for the human body from pathogens. The development of general protein and antibody-specific pre-trained language models both facilitate antibody prediction tasks. However, few studies comprehensively explore the representation capability of distinct pre-trained language models on different antibody problems. Here, to investigate the problem, we aim to answer the following key questions: (1) How do pre-trained language models perform in antibody tasks with different specificity? (2) How many benefits will the model gain if we introduce the specific biological mechanism to the pre-training process? (3) Do the learned antibody pre-trained representations make sense in real-world antibody problems, like drug discovery and immune process understanding? Previously, no benchmark available largely hindered the study to answer these questions. To facilitate the investigation, we provide an AnTibody Understanding Evaluation (ATUE) benchmark. We comprehensively evaluate the performance of protein pre-trained language models by empirical study along with conclusions and new insights. Our ATUE and code is released at https://github.com/dqwang122/EATLM.

bioinformatics↗

bioRxiv2022

Biphasic curvature-dependence of cell migration inside microcylinders: persistent randomness versus directionality

Cell-scale curvature plays important roles in controlling cell and tissue behaviors. However, these roles have not been well quantified, and the underlying mechanisms remain elusive. We combine experiments with theory to study systematically the curvature-dependence of cell migration inside PDMS microcylinders. We find that persistence is positively correlated with speed, following the universal speed-persistence coupling relation, i.e., faster cells turn less. Cell migration inside microcylinders is anisotropic and depends on curvature in a biphasic manner. At small curvatures, as curvature increases, the average speed and anisotropy both increase, but surprisingly, the average persistence decreases. Whereas as the curvature increases over some threshold, cells detach from the surface, the average speed and anisotropy both decrease sharply but the average persistence increases. Moreover, interestingly, cells are found to leave paxillins along their trajectories (on curved but not planar surfaces), facilitating the assembly of focal adhesions of following cells. We propose a minimal model for the biphasic curvotaxis based on three mechanisms: the persistent random "noise", the bending penalty of stress fibers, and the cell-surface adhesion. The findings provide a novel and general perspective on directed cell migration in the widely existing curved microenvironment of cells in vivo.

biophysics↗

bioRxiv2022

Origin, evolution and diversification of plant mechanosensitive channel of small conductance-like (MSL) proteins

Mechanosensitive (MS) ion channels provide efficient molecular mechanism for transducing mechanical forces into intracellular ion fluxes in all kingdoms of life. The mechanosensitive channel of small conductance (MscS) was one of the best-studied MS channels and its homologs (MSL, MscS-like) were widely distributed in cell-walled organisms. However, the origin, evolution and expansion of MSL proteins in plants are still not clear. Here, we identified more than 2100 MSL proteins from 176 plants and conducted a broad-scale phylogenetic analysis. The phylogenetic tree showed that plant MSL proteins were divided into three groups (I, II and III) prior to the emergence of chlorophytae algae, which was consistent with their specific subcellular localization. MSL proteins were distributed unevenly into each of plant species, and four parallel expansion was identified in angiosperms. In Brassicaceae, most MSL duplicates were derived by whole-genome duplication (WGD)/segmental duplications. Finally, a hypothetical evolutionary model of MSL proteins in plants was proposed based on phylogeny. Our studies illustrate the evolutionary history of the MSL proteins and provide a guide for future functional diversity analyses of these proteins in plants.

bioinformatics↗

bioRxiv2022

HSPB1 facilitates chemoresistance through inhibiting ferroptotic cancer cell death and regulating NF-κB signaling pathway in breast cancer

Chemoresistance is one of the major causes of therapeutic failure and poor prognosis for breast cancer patients, especially for triple-negative breast cancer patients. However, the underlying mechanism remains elusive. Here, we identified novel functional roles of heat shock protein beta-1 (HSPB1), regulating the chemoresistance and ferroptotic cell death in breast cancer. Based on TCGA and GEO databases, HSPB1 expression was upregulated in breast cancer tissues and associated with poor prognosis of breast cancer patients, which was considered as an independent prognostic factor for breast cancer. Functional assays revealed that HSPB1 could promote cancer growth and metastasis in vitro and in vivo. Furthermore, HSPB1 facilitated doxorubicin resistance through protecting breast cancer cells from drug-induced ferroptosis. Mechanistically, HSPB1 could bind with Ik{beta}- and promote its ubiquitination-mediated degradation, leading to increased nuclear translocation and activation of NF-{kappa}B signaling. In addition, HSPB1 overexpression led to enhanced secretion of IL6, which further facilitated breast cancer progression. These findings revealed that HSPB1 upregulation might be a key driver to progression and chemoresistance through regulating ferroptosis in breast cancer, while targeting HSPB1 could be an effective strategy against breast cancer.

cancer biology↗

bioRxiv2022

Dear-DIAXMBD: deep autoencoder for data-independent acquisition proteomics

Data-independent acquisition (DIA) technology for protein identification from mass spectrometry and related algorithms is developing rapidly. The spectrum-centric analysis of DIA data without the use of spectra library from data-dependent acquisition (DDA) data represents a promising direction. In this paper, we proposed an untargeted analysis method, Dear-DIAXMBD, for direct analysis of DIA data. Dear-DIAXMBD first integrates the deep variational autoencoder and triplet loss to learn the representations of the extracted fragment ion chromatograms, then uses the k-means clustering algorithm to aggregate fragments with similar representations into the same classes, and finally establishes the inverted index tables to determine the precursors of fragment clusters between precursors and peptides, and between fragments and peptides. We show that Dear-DIAXMBD performs superiorly with the highly complicated DIA data of different species obtained by different instrument platforms. Dear-DIAXMBD is publicly available at https://github.com/jianweishuai/Dear-DIA-XMBD.

bioinformatics↗

bioRxiv2022

Recovery of structural integrity of epithelial monolayer in response to massive apoptosis-induced defects

Apoptosis exists ubiquitously in organisms and plays an essential role in maintaining the homeostasis of functional tissues. While the signaling pathway of cell apoptosis has been widely studied, the mechanism of how apoptotic cells regulate the structural homeostasis of a living tissue still remains largely elusive. Using a functional epithelial monolayer as a model system, we find that the integrity of the epithelium is interrupted by apoptosis-induced defects, with an increasing permeability to small molecules across the epithelium. The defects promote a structural reorganization through enhanced cell spreading and migratory dynamics, resulting in a quick recovery of epithelium integrity. Moreover, we show the epithelial monolayer remodeling is driven by local enhanced traction force after apoptosis, which triggers the process of fluidization and mesenchymal-like migration. Our results show the quick recovery of epithelial homeostasis when being interrupted by cell apoptosis, and indicate the importance of apoptosis-induced mechanical force in mediating cell behaviors to maintain the structural integrity of epithelium.

biophysics↗

bioRxiv2022

Spatiotemporal heterogeneity and the long-term impact of meteorological , environmental and socio-economic factors of scrub typhus in China from 2012 to 2018

Large-scale outbreaks of scrub typhus combined with the emergence of this vector-borne rickettsiosis in new areas indicate that this disease remains seriously neglected. This study aimed to explore the long-term changes and regional leading factors of scrub typhus in China, so as to provide fresh insights for the prevention and control of this disease. In this study, a Bayesian space-time hierarchical model (BSTHM) was used to identify the long-term spatiotemporal heterogeneity of scrub typhus and quantify the association between meteorological factors and scrub typhus in southern and northern China from 2012 to 2018. GeoDetector model was used to quantify the dominant forces of environmental and socioeconomic factors in the Northern and the Southern China. Scrub typhus often appeared in summer and autumn (June to November), and epidemically peaked in October, with obvious temporal seasonality. Spatially, the hot spots (high-risk regions) were concentrated in the south, on the contrary the cold spots (low-risk regions) in the north. In addition, the main meteorological factor, average temperature, gave a significant impact in both areas. The average temperature increased by 1 {degrees}C, resulting in a decrease of 1.10% in southern China and an increase of 0.96% in northern China in the risk of scrub typhus. The determinant environmental and socio-economic factors of scrub typhus in the two areas were altitude and per capita GDP, with q-values of 0.91 and 0.87, respectively. Meteorological, environmental and socio-economic factors had a significant impact on the distribution of scrub typhus, with obvious seasonality and spatial heterogeneity. This study provides helpful suggestions and basis for reasonably allocating resources and controlling the occurrence of scrub typhus. Author summaryScrub typhus is a natural-focus disease caused by the bite of chigger mite larval. In this study, we use BSTHM to capture the overall temporal trend and spatial hot spots of scrub typhus, and quantify the relationship between the disease and major meteorological factors. Meanwhile, Geodetector model was used to quantify the influence of other potential risk factors and estimate the spatio-temporal heterogeneity of scrub typhus. The results showed that scrub typhus had significant seasonality, with a q value of 0.52, and spatial heterogeneity, with a q-value of 0.64. Scrub typhus mainly occurred in summer and autumn, and high-risk areas were mainly distributed in southern China (Yunnan, Hainan and Guangdong). These heterogeneity were closely related to the vector and host. Whether in the South or the north, scrub typhus was closely related to risk factors such as temperature, per capita GDP, NDVI, altitude and the percentage of children aged 0-14. These results suggest that the relevant departments should strengthen the monitoring of the ecological environment, the host and vector of Orientia tsutsugamushi, and strengthen the risk awareness, so as to prevent and control the possible increased risk of scrub typhus under these meteorological, environmental and socio-economic conditions. Considering the differences in different regions, resources should be allocated reasonably.

ecology↗

bioRxiv2022

A Multidimensional Approach to Understanding the Emergence of Sex Differences in Internalizing Symptoms in Adolescence

Women are more vulnerable to internalizing disorders (e.g., depression and anxiety). This study took an integrative, developmental approach to investigate multidimensional factors associated with the emergence of sex differences in internalizing symptoms, using data from the Adolescent Brain Cognitive Development (ABCD) study. Indices of sex hormone levels (dehydroepiandrosterone, testosterone, and estradiol), physical pubertal development, task-based functional brain activity, family conflict, and internalizing symptoms were drawn from the ABCD studys baseline sample (9-to 10-year-old; N = 11,844). Principal component analysis served as a data-driven dimensionality reduction technique on the internalizing subscales to yield a single robust measure of internalizing symptoms. Moderated mediation analyses assessed whether associations between known risk factors and internalizing symptoms vary by sex. Results revealed direct and indirect effects of physical pubertal development on internalizing symptoms through family conflict across sexes. No effects were found of sex hormone levels or amygdala response to fearful faces on internalizing symptoms. Females did not report overall greater internalizing symptoms relative to males, suggesting that internalizing symptoms have not yet begun to increase in females at this age. Findings provide an essential baseline for future longitudinal research on the endocrine, neurocognitive, and psychosocial factors associated with sex differences in internalizing symptoms.

neuroscience↗

bioRxiv2022

A Single-Cell Molecular Atlas of White Adipose Tissue Shows Differences in Myeloid and Lymphoid Cell Polarization in Type 2 Diabetes and HIV Infection

Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and significant alterations in the SAT immune environment compared with the general population. We generated a comprehensive SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH with a spectrum of metabolic health. Glucose intolerance was associated with increased lipid-associated macrophages and CD4+ and CD8+ T effector memory cells, and decreased perivascular macrophages. We observed a coordinated intercellular regulatory program which enriched for genes related to inflammation and lipid-processing across multiple cell types as glucose intolerance increased. Increased CD4+ effector memory tissue resident cells most strongly associated with altered expression of adipocyte genes critical for lipid metabolism and cellular regulation. Many of these findings were present in a separate group of 32 diabetic HIV-negative persons, suggesting these changes are not specific to HIV.

immunology↗

bioRxiv2021

The Nerve Growth Factor IB-like Receptor Nurr1 (NR4A2) recruits CoREST transcription repressor complexes to silence HIV following proviral reactivation in microglial cells

Human immune deficiency virus (HIV) infection of microglial cells in the brain leads to chronic neuroinflammation, which is antecedent to the development of HIV-associated neurocognitive disorders (HAND) in the majority of patients. Productively HIV infected microglia release multiple neurotoxins including proinflammatory cytokines and HIV proteins such as envelope glycoprotein (gp120) and transactivator of transcription (Tat). However, powerful counteracting silencing mechanisms in microglial cells result in the rapid shutdown of HIV expression to limit neuronal damage. Here we investigated whether the Nerve Growth Factor IB-like nuclear receptor Nurr1 (NR4A2), which is a repressor of inflammation in the brain, acts to directly restrict HIV expression. HIV silencing was substantially enhanced by Nurr1 agonists in both immortalized human microglial cells (h{micro}glia) and induced pluripotent stem cells (iPSC)-derived human microglial cells (iMG). Overexpression of Nurr1 led to viral suppression, whereas by contrast, knock down (KD) of endogenous Nurr1 blocked HIV silencing. Chromatin immunoprecipitation (ChIP) assays showed that Nurr1 mediates recruitment of the CoREST/HDAC1/G9a/EZH2 transcription repressor complex to HIV promoter resulting in epigenetic silencing of active HIV. Transcriptomic studies demonstrated that in addition to repressing HIV transcription, Nurr1 also downregulated numerous cellular genes involved in inflammation, cell cycle, and metabolism, thus promoting HIV latency and microglial homoeostasis. Thus, Nurr1 plays a pivotal role in modulating the cycles of proviral reactivation by cytokines and potentiating the proviral transcriptional shutdown. These data highlight the therapeutic potential of Nurr1 agonists for inducing HIV silencing and microglial homeostasis and amelioration of the neuroinflammation associated with HAND. AUTHOR SUMMARYHIV enters the brain almost immediately after infection where it infects perivascular macrophages, microglia and, to a less extent, astrocytes. In previous work using an immortalized human microglial cell model, we observed that integrated HIV constantly underwent cycles of reactivation and subsequent silencing. In the present study, we found that the Nurr1 nuclear receptor is a key mediator of HIV silencing. The functional activation of Nurr1 by specific agonists, or the over expression of Nurr1, resulted in rapid silencing of activated HIV in microglial cells. Global gene expression analysis confirmed that Nurr1 not only repressed HIV expression but also regulated numerous genes involved in microglial homeostasis and inflammation. Thus, Nurr1 is pivotal for HIV silencing and repression of inflammation in the brain and is a promising therapeutic target for treatment of HAND.

microbiology↗

bioRxiv2021

Inhibition of SAR S-CoV-2 infection and replication by lactoferrin, MUC1 and α-lactalbumin identified in human breastmilk

The global pandemic of COVID-19 caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection confers great threat to the public health. Human breastmilk is an extremely complex with nutritional composition to nourish infants and protect them from different kinds of infection diseases and also SARS-CoV-2 infection. Previous studies have found that breastmilk exhibited potent antiviral activity against SARS-CoV-2 infection. However, it is still unknown which component(s) in the breastmilk is responsible for its antiviral activity. Here, we identified Lactoferrin (LF), MUC1 and -Lactalbumin (-LA) from human breastmilk by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and in vitro confirmation that inhibited SARS-CoV-2 infection and analyzed their antiviral activity using the SARS-CoV-2 pseudovirus system and transcription and replication-competent SARS-CoV-2 virus-like-particles (trVLP) in the Huh7.5, Vero E6 and Caco-2-N cell lines. Additionally, we found that LF and MUC1 could inhibit viral attachment, entry and post-entry replication, while -LA just inhibit viral attachment and entry. Importantly, LF, MUC1 and -LA possess potent antiviral activities towards not only wild-type but also variants such as B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma) and B.1.617.1 (kappa). Moreover, LF from other species (e.g., bovine and goat) is still capable of blocking viral attachment to cellular heparan sulfate. Taken together, our study provided the first line of evidence that human breastmilk components (LF, MUC1 and -LA) are promising therapeutic candidates warranting further development or treatingVID-19 given their exceedingly safety levels.

microbiology↗

bioRxiv2021

Both Simulation and Sequencing Data Reveal Multiple SARS-CoV-2 Variants Coinfection in COVID-19 Pandemic

SARS-CoV-2 is a single-stranded RNA betacoronavirus with a high mutation rate. The rapidly emerged SARS-CoV-2 variants could increase the transmissibility, aggravate the severity, and even fade the vaccine protection. Although the coinfections of SARS-CoV-2 with other respiratory pathogens have been reported, whether multiple SARS-CoV-2 variants coinfection exists remains controversial. This study collected 12,986 and 4,113 SARS-CoV-2 genomes from the GISAID database on May 11, 2020 (GISAID20May11) and April 1, 2021 (GISAID21Apr1), respectively. With the single-nucleotide variants (SNV) and network clique analysis, we constructed the single-nucleotide polymorphism (SNP) coexistence networks and noted the SNP number of the maximal clique as the coinfection index. The coinfection indices of GISAID20May11 and GISAID21Apr1 datasets were 16 and 34, respectively. Simulating the transmission routes and the mutation accumulations, we discovered the linear relationship between the coinfection index and the coinfected variant number. Based on the linear relationship, we deduced that the COVID-19 cases in the GISAID20May11 and GISAID21Apr1 datasets were coinfected with 2.20 and 3.42 SARS-CoV-2 variants on average. Additionally, we performed Nanopore sequencing on 42 COVID-19 patients to explore the virus mutational characteristics. We found the heterozygous SNPs in 41 COVID-19 cases, which support the coinfection of SARS-CoV-2 variants and challenge the accuracy of phylogenetic analysis. In conclusion, our findings reported the coinfection of SARS-CoV-2 variants in COVID-19 patients, demonstrated the increased coinfected variants number in the epidemic, and provided clues for the prolonged viral shedding and severe symptoms in some cases.

bioinformatics↗

bioRxiv2021

Rational Discovery of New Folds for Human Solute Carrier Proteins

Solute carrier (SLC) superfamily is the largest group responsible for transmembrane transport of substances in human cells. It includes more than 400 members which are organized into 65 families according to their physiological function and sequence similarity. Different families of solute transporters can adopt the same or different folds that determine the working mechanism and reflect the evolutionary relationship between SLC members. Analysis of structural data in literatures shows that there are 13 different folds in the solute carrier superfamily covering 40 families and 343 members. To further study their working mechanism, we systematically explored the SLC superfamily to look for more folds. Based on our results, at least three new folds were found for SLC superfamily, and one was experimentally verified in the SLC44 family. Our work has laid a foundation and provided important insights for the systematic and comprehensive study on the structure and function of solute carriers.

biophysics↗

bioRxiv2021

Functional connectomics spanning multiple areas of mouse visual cortex

To understand the brain we must relate neurons functional responses to the circuit architecture that shapes them. Here, we present a large functional connectomics dataset with dense calcium imaging of a millimeter scale volume. We recorded activity from approximately 75,000 neurons in primary visual cortex (VISp) and three higher visual areas (VISrl, VISal and VISlm) in an awake mouse viewing natural movies and synthetic stimuli. The functional data were co-registered with a volumetric electron microscopy (EM) reconstruction containing more than 200,000 cells and 0.5 billion synapses. Subsequent proofreading of a subset of neurons in this volume yielded reconstructions that include complete dendritic trees as well the local and inter-areal axonal projections that map up to thousands of cell-to-cell connections per neuron. Here, we release this dataset as an open-access resource to the scientific community including a set of tools that facilitate data retrieval and downstream analysis. In accompanying papers we describe our findings using the dataset to provide a comprehensive structural characterization of cortical cell types1-3 and the most detailed synaptic level connectivity diagram of a cortical column to date2, uncovering unique cell-type specific inhibitory motifs that can be linked to gene expression data4. Functionally, we identify new computational principles of how information is integrated across visual space5, characterize novel types of neuronal invariances6 and bring structure and function together to decipher a general principle that wires excitatory neurons within and across areas7, 8.

neuroscience↗

bioRxiv2020

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic and metabolomic analysis, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+/NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, the antioxidant NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a "shock and kill effect" decreasing proviral DNA in cells from people-living-with-HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies.

immunology↗