A selective Fibroblast Growth Factor Receptor 1/2 PROTAC degrader with antitumor activity.

The aberrant activation of fibroblast growth factor receptor (FGFR) acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised due to low selectivity and side effects. Here, we report the selective FGFR1/2-targeting proteolysis targeting chimeric (PROTAC), BR-cpd7 that displays significant isoform specificity to FGFR1/2 with DC50 values around 10 nM, while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no anti-proliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.

The Arabidopsis RTH plays an important role in regulation of iron (Fe) absorption and transport.

KEY MESSAGE: RTH may activate Fe assimilation related genes to promote Fe absorption, transport and accumulation in Arabidopsis. Iron (Fe) is an important nutrient element. The Fe absorption and transport in plants are well investigated over the past decade. Our previous work indicated that RTE1-HOMOLOG (RTH), the homologous gene of reversion-to-ethylene sensitivity 1 (RTE1), plays a role in ethylene signaling pathway. However, its function in Fe absorption and transport is largely unknown. In the present study, we found that RTH was expressed in absorptive tissue and conducting tissue, including root hairs, root vascular bundle, and leaf veins. Under high Fe concentration, the seedling growth of rth-1 mutant was better, while the RTH overexpression lines were retarded compared to the wild type (Col-0). When treated with EDTA-Fe3+ (400 µM), the chlorophyll content and ion leakage rate were higher and lower in rth-1 than those of Col-0, respectively. By contrast, the chlorophyll contents and ion leakage rates of RTH overexpression lines were decreased and hastened compared with Col-0, respectively. Fe measurement indicated that the Fe contents of rth-1 were lower than those of Col-0, whereas those of RTH overexpression lines were comparably higher. Gene expression analysis revealed that Fe absorption and transport genes AHA2, IRT1, FIT, FPN1, and YSL1 decreased in rth-1 but increased in RTH overexpression lines compared with Col-0. Additionally, Y2H (yeast two-hybrid) and BiFC (bimolecular fluorescence complementation) assays showed that RTH can physically interact with hemoglobin 1 (HB1) and HB2. All these findings suggest that RTH may play an important role in regulation of Fe absorption, transport, and accumulation in Arabidopsis.

Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression.

Respiratory syncytial virus (RSV) is a global healthcare problem, causing respiratory illness in young children and elderly individuals. Our knowledge of the host pathways that define susceptibility to infection and disease severity are limited. Hypoxia inducible factors (HIFs) define metabolic responses to low oxygen and regulate inflammatory responses in the lower respiratory tract. We demonstrate a role for HIFs to suppress RSV entry and RNA replication. We show that hypoxia and HIF prolyl-hydroxylase inhibitors reduce the expression of the RSV entry receptor nucleolin and inhibit viral cell-cell fusion. We identify a HIF regulated microRNA, miR-494, that regulates nucleolin expression. In RSV-infected mice, treatment with the clinically approved HIF prolyl-hydroxylase inhibitor, Daprodustat, reduced the level of infectious virus and infiltrating monocytes and neutrophils in the lung. This study highlights a role for HIF-signalling to limit multiple aspects of RSV infection and associated inflammation and informs future therapeutic approaches for this respiratory pathogen.

Cohort profile: Beijing Healthy Aging Cohort Study (BHACS).

The Beijing Healthy Aging Cohort Study (BHACS) was established to supplement the limited data of a large representative cohort of older people based on the general population and was designed to evaluate the prevalence, incidence, and natural history of cognitive decline, functional disability, and conventional vascular risk factors. The aim was to determine the evolution of these conditions by estimating the rates and determinants of progression and regression to adverse outcomes, including dementia, cardiovascular events, cancer, and all-cause death. It can therefore provide evidence to help policy makers develop better policies to promote healthy aging in China. BHACS consisted of three cohorts (BLSA, CCHS-Beijing, and BECHCS) in Beijing with a total population of 11 235 (6281 in urban and 4954 in rural areas) and an age range of 55 years or older (55-101 years) with a mean age of 70.35 ± 7.71 years (70.69 ± 7.62 years in urban and 69.92 ± 7.80 years in rural areas). BHACS-BLSA conducted the baseline survey in 2009 with a multistage stratification-random clustering procedure for people aged 55 years or older; BHACS-CCHS-Beijing conducted the baseline survey in 2013-2015 with a stratified multistage cluster random sampling method for people aged 55 years or older; and BHACS-BECHCS conducted the baseline survey in 2010-2014 with two-stage cluster random sampling method for people aged 60 years or older. Data were collected through questionnaires, physical measurements, and laboratory analyses. Topics covered by BHACS include a wide range of physical and mental health indicators, lifestyles and personal, family, and socio-economic determinants of health. There are no immediate plans to make the cohort data freely available to the public, but specific proposals for further collaboration are welcome. For further information and collaboration, please contact the corresponding author Yao He (e-mail: yhe301@x263.net).

Therapeutic vaccination following early antiretroviral therapy elicits highly functional T cell responses against conserved HIV-1 regions.

'Kick and kill' cure strategies aim to induce HIV protein expression in latently infected cells (kick), and thus trigger their elimination by cytolytic T cells (kill). In the Research in Viral Eradication of HIV Reservoirs trial (NCT02336074), people diagnosed with primary HIV infection received immediate antiretroviral therapy (ART) and were randomised 24 weeks later to either a latency-reversing agent, vorinostat, together with ChAdV63.HIVconsv and MVA.HIVconsv vaccines, or ART alone. This intervention conferred no reduction in HIV-1 reservoir size over ART alone, despite boosting virus-specific CD4+ and CD8+ T cells. The effects of the intervention were examined at the cellular level in the two trial arms using unbiased computational analysis of polyfunctional scores. This showed that the frequency and polyfunctionality of virus-specific CD4+ and CD8+ T cell populations were significantly increased over 12 weeks post-vaccination, compared to the ART-only arm. HIV-specific IL-2-secreting CD8+ T cells also expanded significantly in the intervention arm and were correlated with antiviral activity against heterologous HIV in vitro. Therapeutic vaccination during ART commenced in primary infection can induce functional T cell responses that are phenotypically similar to those of HIV controllers. Analytical therapy interruption may help determine their ability to control HIV in vivo.

HLA-E-restricted SARS-CoV-2-specific T cells from convalescent COVID-19 patients suppress virus replication despite HLA class Ia down-regulation.

Pathogen-specific CD8+ T cell responses restricted by the nonpolymorphic nonclassical class Ib molecule human leukocyte antigen E (HLA-E) are rarely reported in viral infections. The natural HLA-E ligand is a signal peptide derived from classical class Ia HLA molecules that interact with the NKG2/CD94 receptors to regulate natural killer cell functions, but pathogen-derived peptides can also be presented by HLA-E. Here, we describe five peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that elicited HLA-E-restricted CD8+ T cell responses in convalescent patients with coronavirus disease 2019. These T cell responses were identified in the blood at frequencies similar to those reported for classical HLA-Ia-restricted anti-SARS-CoV-2 CD8+ T cells. HLA-E peptide-specific CD8+ T cell clones, which expressed diverse T cell receptors, suppressed SARS-CoV-2 replication in Calu-3 human lung epithelial cells. SARS-CoV-2 infection markedly down-regulated classical HLA class I expression in Calu-3 cells and primary reconstituted human airway epithelial cells, whereas HLA-E expression was not affected, enabling T cell recognition. Thus, HLA-E-restricted T cells could contribute to the control of SARS-CoV-2 infection alongside classical T cells.

Magnetic CuFe2O4 nanoparticles anchored on N-doped carbon for activated peroxymonosulfate removal of oxytetracycline from water: Radical and non-radical pathways.

In this work, magnetic CuFe2O4 was prepared for the removal of oxytetracycline (OTC) by a self-propagating combustion synthesis method. Almost complete degradation (99.65%) of OTC was achieved within 25 min at [OTC]0 = 10 mg/L, [PMS]0 = 0.05 mM, CuFe2O4 = 0.1 g/L under pH = 6.8 at 25 °C for deionized water. Specially, the addition CO32- and HCO3- induced the CO3•- appearance enhancing the selective degradation to electron-rich OTC molecule. The prepared CuFe2O4 catalyst exhibited desirable OTC removal rate (87.91%) even in hospital wastewater. The reactive substances were analyzed by free radical quenching experiments and electron paramagnetic resonance (EPR), and the results demonstrated that 1O2 and •OH were the main active substances. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the intermediates produced during the degradation of OTC and thus to speculate on the possible degradation pathways. Ecotoxicological studies were conducted to unveil large-scale application prospect.

Immune mobilising T cell receptors redirect polyclonal CD8+ T cells in chronic HIV infection to form immunological synapses.

T cell exhaustion develops in human immunodeficiency virus (HIV) infection due to chronic viral antigenic stimulation. This adaptive response primarily affects virus-specific CD8+ T cells, which may remain dysfunctional despite viral load-reducing antiretroviral therapy; however, abnormalities may also be evident in non-HIV-specific populations. Both could limit the efficacy of cell therapies against viral reservoirs. Here, we show that bulk (polyclonal) CD8+ T cells from people living with HIV (PLWH) express proposed markers of dysfunctional HIV-specific T cells at high levels yet form lytic immunological synapses (IS) and eliminate primary resting infected (HIV Gaglo) CD4+ T cells, when redirected by potent bispecific T cell-retargeting molecules, Immune mobilising monoclonal T cell receptors (TCR) Against Virus (ImmTAV). While PLWH CD8+ T cells are functionally impaired when compared to CD8+ T cells from HIV-naïve donors, ImmTAV redirection enables them to eliminate Gaglo CD4+ T cells that are insensitive to autologous HIV-specific cytolytic T cells. ImmTAV molecules may therefore be able to target HIV reservoirs, which represent a major barrier to a cure.

Construction and evaluation of detachable bone-targeting MOF carriers for the delivery of proteasome inhibitors.

Tumor bone metastasis is an important cause of tumor recurrence and death. Although bone-targeting nanoparticles decorated with targeting ligands have shown good affinity for bone tissues with the properties of adhesion to the bone matrix, it is not easy to detach from the surface of the bone matrix in the tumor-bone microenvironment, attributed to the robust coordination force between the targeting ligands, such as bisphosphates with bone-deposited calcium. This may hinder the transport of nanoparticles from bone tissue to bone metastatic tumors. In this research, we designed a bone-targeting nanocarrier with detachable bone-targeting character for the therapy of bone metastases. The nanoparticles were constructed by using ZIF-8 and bone-targeting and MMP enzyme sensitive polypeptide-modified hyaluronic acid as a carrier and proteasome inhibitor Bortezomib (BTZ) as cargo. The results show that the constructed D8-M3-HA-ZIF8@BTZ nanoparticles possessed several favorable properties such as good colloidal stability, acid-sensitive drug release, D8 peptide mediated bone targeting and MMP enzyme-responsive desorption. Besides, nanoparticle endocytosis and cytotoxicity were enhanced through HA-mediated targeting to CD44 over-expressing tumor cells. Altogether, this study provides a potential cascade targeting strategy for improving the delivery effects of bone targeted nanoparticles for the delivery of proteasome inhibitors.

Facile construction of high-performance 3D Co2C-doped CoAl2O4 fiber composites for capturing and decomposing tetracycline from aqueous solution.

Herein, novel 3D hollow-carved Co2C-doped CoAl2O4 fiber composites (3D-CA-FC) were successfully synthesized via a simple-green pyrolysis method and exhibited remarkably outstanding elimination performance for tetracycline (TC) by adsorption and degradation. The results indicated that the TC adsorption process of the samples could be accurately described by the pseudo-second-order and Langmuir isothermal model, and the maximum TC uptake reached up to 1889.63 mg/g under neutral conditions. Meanwhile, 3D-CA-FC showed good affinity for TC and its adsorption capacity was greatly promoted due to the presence of humic acid, CO32- ion and weakly alkaline environment. About complete degradation of TC could be completed within 60 min under suitable conditions. A significant improvement of catalyst rate was observed after the addition of CO32- ion, because of the selective degradation of CO3•- to TC. BET, XPS and FT-IR analysis indicated that the mechanisms of TC uptake can be ascribed to pore-filling, H-bonds and complexation. Radical trapping experiments showed that 1O2 should serve as predominant contributions, and SO4•- and •OH also played a role in the degradation process. This study provides some inspiration for the construction of 3D-CA-FC as a novel and promising bifunctional material for the elimination of contaminants in water treatment.

Bifunctional two-dimensional copper-aluminum modified filter paper composite for efficient tetracycline removal: Synergy of adsorption and reusability by degradation.

Herein, bifunctional two-dimensional copper-aluminum modified filter paper composite (2D-Cu/Al-C) was successfully prepared by simple calcination and showed ultrahigh adsorption performance and degradation potential. The adsorption removal of TC on 2D-Cu/Al-C all exceeded 92.2% under solution conditions of 10-200 mg/L TC, 100 mg/L 2D-Cu/Al-C, pH 8 and 298 K. The pseudo-second-order kinetic and Langmuir models better fitted the kinetic and isotherm data via spontaneous and exothermic process, and the maximum capacity of the 2D-Cu/Al-C was 2391.78 mg/g. Additionally, 2D-Cu/Al-C showed desired specific adsorption for TC (TC: 98.7%, norfloxacin: 5.8%, sulfamethoxazole: 2.1%, and ciprofloxacin: 1.8%) and it could effectively adsorbed TC even in the binary system (various coexisting ions or natural organic matter). After TC adsorbed on adsorbent was mineralized into CO2 and H2O by adding peroxydisulfate to generate high electrode potential radical in another limited systems, the 2D-Cu/Al-C still had ∼89.12% on TC removal (initial concentration of 50 mg/L) after five experimental cycles. Zeta potential, FT-IR and XPS results indicated that the multi-adsorption mechanism, including electrostatic interactions, complexation, and H-bonds, played a vital role in the fast and efficient adsorption process. Thus, the way of combining adsorption and regeneration via degradation are green, non-polluting strategy which are expected to be applied for water purification in future environmental remediation.

Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia.

Preeclampsia is a leading contributor to increased maternal morbidity and mortality in the perinatal period. Increasing evidence demonstrates that ferroptosis is an essential mechanism for the pathogenesis of preeclampsia. Elabela is a novel small-molecule polypeptide, mainly expressed in embryonic and transplacental tissues, with an ability to promote cell proliferation and invasion. However, its specific regulatory mechanism in preeclampsia has not been completely elucidated. In this study, we first reveal an increased grade of ferroptosis accompanied by a downregulation of the expression of Elabela in preeclampsia placentas. We then confirm the presence of a ferroptosis phenotype in the placenta of the mouse PE-like model, and Elabela can reduce ferroptosis in the placenta and improve adverse pregnancy outcomes. Furthermore, we demonstrate that targeting Elabela alleviates the cellular dysfunction mediated by Erastin promoting increased lipid peroxidation in vitro. Subsequent mechanistic studies suggest that Elabela increases FTH1 levels by inhibiting the ferritinophagy pathway, and consequently chelates the intracellular labile iron pool and eventually arrests ferroptosis. In conclusion, Elabela deficiency exacerbates ferroptosis in the placenta, which is among the potential mechanisms in the pathogenesis of preeclampsia. Targeting the Elabela-ferritinophagy-ferroptosis signaling axis provides a new therapeutic intervention strategy to alleviate preeclampsia.

Effects of ozone water irrigation and spraying on physiological characteristics and gene expression of tomato seedlings.

Tomato seedlings were used as experimental materials and treated with 1.0, 2.0, 3.0, and 4.0 mg/L ozone water irrigation and 0.2, 0.4, 0.6, and 0.8 mg/L ozone water spray treatments. Indexes including the malondialdehyde (MDA) content, superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), activities, soil and plant analysis development (SPAD) value, and nitrogen content of leaves were measured. Furthermore, the expression of antioxidant enzyme, chlorophyll synthesis and nitrogen absorption genes was analyzed after optimal ozone water treatment. The results showed that the activities of antioxidant enzymes in tomato leaves were significantly increased, and the MDA content in tomato leaves was significantly reduced by ozone water irrigation and spray treatment, which indicated that ozone water treatment can significantly improve the stress tolerance of tomato seedlings. Ozone water irrigation and spraying could also significantly increase the leaf SPAD value and nitrogen content of tomato seedlings, and the optimal concentrations of ozone water irrigation and spraying were 3.0 mg/L and 0.6 mg/L, respectively. The effect of ozone water irrigation on improving the physiological characteristics of tomato seedlings was better than that of spraying. After treatment with the optimal concentration of ozone water, the relative expression of antioxidant enzyme, chlorophyll synthesis, and nitrogen absorption genes was significantly increased, and the maximum expression level was reached at 12 h. In addition, ozone water irrigation could promote the expression of genes more than ozone water spraying, which was consistent with the improvements in the physiological characteristics of the tomato seedlings.

Incoming HIV virion-derived Gag Spacer Peptide 2 (p1) is a target of effective CD8+ T cell antiviral responses.

Persistence of HIV through integration into host DNA in CD4+ T cells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8+ T cells are triggered to kill infected CD4+ T cells through recognition of histocompatibility leukocyte antigen (HLA) class I-bound peptides derived from incoming virions. However, this has been reported only in individuals with "beneficial" HLA alleles that are associated with superior HIV control. Through interrogation of the pre-integration immunopeptidome, we obtain proof of early presentation of a virion-derived HLA-A∗02:01-restricted epitope, FLGKIWPSH (FH9), located in Gag Spacer Peptide 2 (SP2). FH9-specific CD8+ T cell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4+ T cells prior to virus production in vitro. Our data show that non-beneficial HLA class I alleles can elicit an effective antiviral response through early presentation of HIV virion-derived epitopes and also demonstrate the importance of SP2 as an immune target.

A series of novel carbohydrate-based carbon adsorbents were synthesized by self-propagating combustion for tetracycline removal.

Herein, a series of novel adsorbents derived from glucose, maltose, and starch zinc oxide (ZnO) loaded carbohydrate-based carbon materials (Zn-Cs) were synthesized by a fast and efficient self-propagating combustion synthesis method (SCS). The experimental results show that Zn-Cs exhibits excellent adsorption performance (>375 mg/g) to tetracycline, and the pseudo-second-order model and Freundlich model can better describe the adsorption data. The adsorption capacities of Zn-Cs were over 300 mg/g throughout the wide pH range (6-9), while various coexisting ions in the concentration range of 0-10 mg/L and the presence of humic acid had nearly no impact on the adsorption of tetracycline. Moreover, the adsorption experiment of simulated hospital wastewater shows that the adsorption capacity of Zn-Cs for tetracycline exceeds 185 mg/g. The adsorption mechanism of tetracycline are H-bond, complexation, and conjugation effect. This work provides an efficient, excellent versatility and time-saving strategy for preparing high-performance carbohydrate-based carbon materials for adsorbents.

HLA-E-restricted, Gag-specific CD8+ T cells can suppress HIV-1 infection, offering vaccine opportunities.

Human leukocyte antigen-E (HLA-E) normally presents an HLA class Ia signal peptide to the NKG2A/C-CD94 regulatory receptors on natural killer (NK) cells and T cell subsets. Rhesus macaques immunized with a cytomegalovirus-vectored simian immunodeficiency virus (SIV) vaccine generated Mamu-E (HLA-E homolog)-restricted T cell responses that mediated post-challenge SIV replication arrest in >50% of animals. However, HIV-1-specific, HLA-E-restricted T cells have not been observed in HIV-1-infected individuals. Here, HLA-E-restricted, HIV-1-specific CD8 + T cells were primed in vitro. These T cell clones and allogeneic CD8 + T cells transduced with their T cell receptors suppressed HIV-1 replication in CD4 + T cells in vitro. Vaccine induction of efficacious HLA-E-restricted HIV-1-specific T cells should therefore be possible.

Identification and Characterization of Extrachromosomal Circular DNA in Human Placentas With Fetal Growth Restriction.

Many studies have confirmed that extrachromosomal circular DNAs (eccDNAs/ecDNAs) exist in tumor and normal cells independently of the chromosome and are essential for oncogene plasticity and drug resistance. Studies have confirmed that there are many eccDNAs/ecDNAs in maternal plasma derived from the fetus. Fetal growth restriction (FGR) is a pregnancy-related disease associated with high newborn morbidity and mortality. However, the characteristics and nature of eccDNAs/ecDNAs in FGR are poorly understood. This study aims to deconstruct the properties and potential functions of eccDNAs/ecDNAs in FGR. We performed circle-seq to identify the expression profile of eccDNAs/ecDNAs, analyzed by bioinformatics, and verified by real-time Polymerase Chain Reaction (PCR) combined with southern blot in FGR compared with the normal groups. A total of 45,131 eccDNAs/ecDNAs (including 2,118 unique ones) were identified, which had significantly higher abundance in FRG group than in normal group, and was bimodal in length, peaking at ~146bp and ~340bp, respectively. Gestational age may be one independent factor affecting the production of eccDNAs/ecDNAs, most of which come from genomic regions with high gene density, with a 4~12bp repeat around the junction, and their origin had a certain genetic preference. In addition, some of the host-genes overlapped with non-coding RNAs (ncRNAs) partially or even completely. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that host-genes on the differentially expressed eccDNAs/ecDNAs (DEEECs/DEECs) were mainly enriched in immune-related functions and pathways. The presence of some ecDNAs were verified, and whose variability were consistent with the circle-seq results. We identified and characterized eccDNAs/ecDNAs in placentas with FGR, and elucidated the formation mechanisms and the networks with ncRNAs, which provide a new vision for the screening of new biomarkers and therapeutic targets for FGR.

Self-propagating synthesis of Zn-loaded biochar for tetracycline elimination.

Herein, a novel Zn-loaded biochar (Zn-LBC) originating from Fraxinus pennsylvanica Marsh leaves was successfully prepared through a simple and rapid self-propagating combustion reaction (SHS) and could serve as an efficient adsorbent for tetracycline (TC) elimination from water. The adsorption performance was analyzed via a series of characterizations and batch adsorption experiments. The results showed that the novel adsorbent Zn-LBC exhibited an excellent TC adsorption capacity (159.64 mg/g), which was 2.63 times higher than that of the original biochar (60.78 mg/g). The pseudo-second-order kinetic model and Freundlich isothermal model fit the adsorption data well. It is noteworthy that Zn-LBC had little effect on the adsorption capacity of TC in the 0-10 mg/L various coexisting ion range and presence of humic acid (HA). In addition, the adsorption test of TC using hospital wastewater as the water sample also achieved satisfactory results (raw influent: 52.65 mg/g, final effluent: 85.64 mg/g). FT-IR and XPS investigations showed that the TC adsorption mechanism included surface complexation, π-π interactions, and hydrogen bonds. The results provide new ideas for exploring low-cost and highly efficient modified biochar adsorbent for TC elimination.

Hypoxic microenvironment shapes HIV-1 replication and latency.

Viral replication is defined by the cellular microenvironment and one key factor is local oxygen tension, where hypoxia inducible factors (HIFs) regulate the cellular response to oxygen. Human immunodeficiency virus (HIV) infected cells within secondary lymphoid tissues exist in a low-oxygen or hypoxic environment in vivo. However, the majority of studies on HIV replication and latency are performed under laboratory conditions where HIFs are inactive. We show a role for HIF-2α in restricting HIV transcription via direct binding to the viral promoter. Hypoxia reduced tumor necrosis factor or histone deacetylase inhibitor, Romidepsin, mediated reactivation of HIV and inhibiting HIF signaling-pathways reversed this phenotype. Our data support a model where the low-oxygen environment of the lymph node may suppress HIV replication and promote latency. We identify a mechanism that may contribute to the limited efficacy of latency reversing agents in reactivating HIV and suggest new strategies to control latent HIV-1.