- Review
- Open access
- Published:
Oxygen: viral friend or foe?
Virology Journal volume 17, Article number: 115 (2020)
Abstract
The oxygen levels organ and tissue microenvironments vary depending on the distance of their vasculature from the left ventricle of the heart. For instance, the oxygen levels of lymph nodes and the spleen are significantly lower than that in atmospheric air. Cellular detection of oxygen and their response to low oxygen levels can exert a significant impact on virus infection. Generally, viruses that naturally infect well-oxygenated organs are less able to infect cells under hypoxic conditions. Conversely, viruses that infect organs under lower oxygen tensions thrive under hypoxic conditions. This suggests that in vitro experiments performed exclusively under atmospheric conditions ignores oxygen-induced modifications in both host and viral responses. Here, we review the mechanisms of how cells adapt to low oxygen tensions and its impact on viral infections. With growing evidence supporting the role of oxygen microenvironments in viral infections, this review highlights the importance of factoring oxygen concentrations into in vitro assay conditions. Bridging the gap between in vitro and in vivo oxygen tensions would allow for more physiologically representative insights into viral pathogenesis.
Background
Viral infections are heavily dependent on host cells for energy, enzymes and metabolic intermediates for successful replication [134]. Factors that influence the state of a cell, including differential gene expression and pathway activation, could all impact the outcome of viral pathogenesis. One such factor is the oxygen level in the microenvironment in which cells reside. Oxygen plays key roles in respiration, metabolism and energy production. Given the key role of oxygen in cell function, cells have evolved oxygen sensors that regulate the expression of a suite of genes in response to lowered oxygen levels. For this discovery, William Kaelin, Gregg Semenza and Peter Ratcliffe were awarded the 2019 Nobel Prize for Physiology and Medicine. Here, we elaborate upon our understanding of how cells react to different oxygen levels and review how oxygen affects the outcome of viral infection and disease pathogenesis. In general, viruses that naturally infect and replicate in tissues with high oxygen content are impaired by hypoxic environments. Conversely, hypoxia has been shown to increase the infection of viruses that naturally infect organs with lower oxygen tensions.
Main text
Oxygen cascade
Although oxygen is needed by all human cells, not all cells in our bodies receive similar amounts of oxygen. Oxygen levels in most organs, with a few exceptions, are lower than that of atmospheric oxygen (20–21% or 152-160 mmHg). This disparity is largely due to blood transportation through the vascular anatomy and subsequently vascular beds in tissues [55]. Due to its poor solubility in liquids, oxygen is transported around the body by hemoglobin in red blood cells. Each hemoglobin molecule carries up to a maximum of 4 oxygen molecules with its affinity for each oxygen molecule increasing as each of its binding sites is occupied [120]. Oxygen delivery in the human respiratory system depends on several factors such as the partial pressure of oxygen, efficiency of gas exchange, concentration and affinity of hemoglobin to oxygen and cardiac output [92]. The highest oxygen concentration is typically found in the respiratory tract. As respired air enters the trachea and is humidified in the upper respiratory tract, the pressure of oxygen decreases while concentration of water increases, thus altering the partial pressure of oxygen in this gas mixture [92]. Further dilution occurs as oxygen diffuses in and out of arteries. This is best exemplified in organs such as the spleen and liver. In spleens, oxygen concentrations are highest nearest the splenic artery (~ 6%) as compared to locations in the spleen distant from the splenic artery (~ 1%) [16]. In the liver, oxygen tensions range from approximately 12% oxygen surrounding the portal vein to 1% oxygen in the proximity of the central vein [137]. The average oxygen concentrations of different organs observed in humans and animal models are summarized in Table 1. Taken collectively, with the exception of the lungs which are exposed to ambient air, median physiological oxygen tensions of organs are significantly lower than that of atmospheric oxygen tensions. This is known as the oxygen cascade. Thus, physiological oxygen concentrations in which viral infection and replication occur can be significantly different to the level of oxygen in normal air. It is therefore useful to understand how cells adapt to physiological oxygen tension.
The HIF family and molecular mechanisms of oxygen sensing
In microenvironments with lowered oxygen levels, cells regulate the expression of genes, such as those involved in controlling angiogenesis, iron metabolism and glycolysis, to adapt and survive. To understand the cellular response to lowered oxygen levels, investigators focused on the regulation of erythropoietin (EPO), that is known to be induced in response to lowered oxygen to stimulate erythropoiesis. Analysis of the cis-acting sequences involved in EPO induction led to the identification of hypoxia inducible factor (HIF) [130, 143, 144].
The HIF family
HIF transcription factors are basic helix-loop-helix DNA binding proteins of the PER-ARNT-SIM family [143]. HIFs form heterodimers, where alpha subunits HIF1α, HIF2α, HIF3α [39, 49, 130] interact with a constitutively expressed beta subunit HIF1β, also known as the aryl hydrocarbon receptor nuclear translocator 1 (ARNT1) [145]. HIF1α and HIF2α are oxygen sensitive subunits that share 48% genetic sequence homology [63]. Both dimerize with HIF1β during hypoxic conditions to induce gene transcription [39]. HIF3α is distantly related, sharing less sequence homology and function with HIF1α or HIF2α. It has 6 splice variants [49]. Its function remains understudied in comparison to HIF1α and HIF2α although in vitro studies suggest that the prevailing actions of HIF3α variants are inhibitory and constitutes a negative feedback loop for HIF1α and HIF2α [59, 98].
Both HIF1α and HIF2α proteins have multiple conserved domains involved in DNA binding, protein interaction and dimerization, oxygen-dependent degradation (ODD) and transcriptional activity (N-TAD and C-TAD). HIF3α isoforms are shorter and carry only a N-TAD domain together with a leucine zipper motif with unknown function [99, 115]. HIF1β contains no transcriptional activation domains and requires dimerization with HIF1α to induce transcription. With 70, 85 and 100% homology between their basic helix-loop-helix DNA binding and remaining basic domains, it is not surprising that HIF1α and HIF2α binds DNA indistinguishably [136]. While extremely similar in both homology and function, there are subtle differences between HIF1α and HIF2α. The C-TAD domains of HIF1α and HIF2α control target gene transcription through the recruitment of co-factors but target gene selectivity between the 2 proteins have been postulated to arise from the N-TAD domains which recognize distinct transcriptional co- factors [3, 32, 38, 67]. Besides differences in protein domains, the expression of this protein is variable in different cell types. HIF1α is expressed in almost all immune cell types including neutrophils [142], monocytes [12, 131], macrophages [29], dendritic cells [11, 75] and lymphocytes [9, 101]. HIF2α however is only expressed in certain cell types such as endothelial cells [66] and tumor associated macrophages [72].
Immune cells in the circulatory system are exposed to a gradient of oxygen concentrations in the blood, lymphoid organs and areas of inflammation [120, 121]. It is therefore essential for immune cells such as monocytes, macrophages and dendritic cells to rapidly adapt to fluctuating oxygen. HIF1α has indeed been implicated in all facets of the immune response including inflammation [113], responses to bacterial and viral infections [46, 104, 126, 135], immune cell metabolism [28, 103, 111] and lymphoid cell development [19]. HIF1α could thus be a major regulator of infection outcome.
Oxygen sensing mechanisms of HIF1α
HIF1α sensitivity to cellular oxygen tension is largely dependent on post-translational modifications. While HIF1α is constitutively expressed, it is highly regulated by oxygen and has a short half-life of approximately 5 mins [125]. Sufficient oxygen in the cellular environment, such as those in most in vitro experiments, will result in rapid proteasomal degradation of HIF1α in the cytoplasm [38]. An overview of these processes is shown in Fig. 1.
In oxygen rich environments, a family of prolyl hydroxylase domains (PHD1–3) hydroxylate highly conserved proline residues (Pro402 and Pro564) in the ODD domain of HIF1α in an iron-, α-ketogluterate-, ascorbate- and oxygen-dependent manner [12, 29]. This hydroxylation enables the binding of the von-hippel Lindeau (VHL) E3 ubiquitin ligase complex to HIF1α. Ubiquitination of HIF1α then initiates the process of proteasomal degradation. In addition to PHDs, an independent regulatory hydroxylation step by Factor Inhibiting HIF (FIH) hydroxylates an aspargine (Asn803) to interfere with HIF1α ability to recruit and bind to co-factors via its C-TAD domain [30, 44]. Additional negative regulation of HIF1α occurs by acetylation of Lys532 by acetyl transferase arrest-defective 1[77], GSK3β phosphorylation of Ser551, Ser558 and Ser559 [107] and PLK3 phosphorylation of Ser576 and Ser 659 [149]. All these processes contribute to HIF1α destabilization leading to proteasomal degradation of HIF1α, which prevents transcription of hypoxia inducible genes [77, 107, 149]. Clinically, patients with von Hippel-Lindau syndrome, where VHL is defective, have an overproduction of hypoxia-inducible genes encoding for angiogenesis leading to the development of multiple tumors [122].
As PHD and FIH hydroxylation of HIF1α is oxygen-dependent, any decrease in oxygen levels would lead to stabilization and nuclear translocation of HIF1α. This transport occurs when importin-α binds to the nuclear localization signal in the C-terminal NLS of HIF1α, recruit importin-β and initiates nuclear translocation [35]. In the nucleus, HIF1α forms heterodimers with HIF1β. It has been postulated that HIF1β preferentially binds to HIF1α phosphorylated by MAPK243, therefore increasing transcriptional activity of HIF1α. However transcriptional activity requires N-TAD and C-TAD domains to recruit co-factors CBP/p300, SRC-1 and TIF2 to induce efficient transcription of target genes [18, 91]. Through its interaction with CBP/p300, S-nitrosation on cysteine800 has also been shown to increase HIF1α transcription activity [151]. Other co-factors for HIF1α include pyruvate kinase M2 isoform [97] and mediator associated kinase CD8K [45], ATPase/helicase chromatin remodeling factor Pontin [95] and SWI/SNF nucleosome remodeling complex [82].
Transcription of hypoxia-inducible genes occurs when HIF1α/HIF1β heterodimer bind to a core consensus sequence 5′– (A/G) CGTG − 3′ within the hypoxia response element (HRE) at the proximal promoters of target genes [128]. Though the HRE sequence is abundant throughout the human genome, HIF1α only binds to approximately 1% of such sequence [128]. In addition to the HRE, several HIF1α target genes contain a HIF ancillary sequence (HAS) 5′-CAGGT-3′, which is an imperfect inverted repeat of the HRE. Kimura and colleagues have shown that alteration of this sequence affects the HIF1α-induced transcriptional activity of EPO [86, 87]. Interestingly, HIF1α preferentially binds HRE at regions of chromatin with DNaseI hypersensitivity, RNA polymerase II, basal transcriptional activity and histone modifications [105, 128, 148]. This may serve to explain why HIF1α has cell-type specificity in function.
Hypoxia as a consideration for in vitro studies
Stabilization of HIF in cells residing in low oxygen microenvironments drives cellular reprogramming that also affects the availability of pro-viral and anti-viral host factors that collectively determine the outcome of viral infections. For instance, increase in glycolysis has been shown to be favorable for dengue virus (DENV) [41], herpes simplex virus (HSV) [1], human immunodeficiency virus (HIV) [62], rubella virus [7], hepatitis C virus (HCV) [80], influenza [133] and norovirus [116] infection.
A growing body of evidence suggests that, besides glycolysis, many other hypoxia-driven changes will also have important implications not only in the study of viral pathogenesis.
Viruses which lifecycle is inhibited by hypoxia
Viruses that infect the respiratory tract are generally restricted by hypoxia [36]. This restriction potentially impacts the use of recombinant adenoviruses as a vector for cancer vaccine. Hypoxia is an important feature of solid tumors and the ability of oncolytic viruses such as adenoviruses or vesicular stomatitis virus (VSV) to replicate under these low oxygen conditions could be a critical determinant to the success of these therapies. However, in vitro, significantly reduced synthesis of adenovirus (wildtype strain Ad309) viral protein was observed when cells were cultured at 1% oxygen, ultimately leading to lower production of infectious Ad309 compared to experiments in normal air [119]. As tumor hypoxia has been shown (8-10 mmHg) [64], this restriction of adenovirus infection could be a factor in poor intratumoral spread resulting in the limited efficacy observed in clinical trials [150].
Perhaps a more promising oncolytic virus is VSV, which has been shown to overcome hypoxia-induced restrictions in viral protein translation during early infection in vitro [27]. However, renal carcinoma cells (RCC) lacking pVHL, resulting in constitutive HIF activity, showed greater resistance to the cytolytic effect of VSV as compared to wildtype RCC. Gene expression profiling under these conditions indicates that HIF enhances IFNβ upon VSV infection. This suggests that HIF could play an antiviral response against VSV, and should be an important consideration when used as an oncolytic viral therapy [70] (Table 2).
Viruses enhanced by hypoxia
On the other hand, a multitude of viruses replicate in organs with oxygen microenvironments significantly lower than that of atmospheric air. To establish successful infection, these pathogens would have evolved to thrive in cells adapted to such oxygen microenvironments. Indeed, low oxygen levels have been shown to be advantageous to a number of viruses (Table 1). Under hypoxic conditions, cells develop a metabolic response to ensure their survival, in part by upregulating anaerobic glycolysis for energy production In hepatocytes, this increase in anaerobic glycolysis directly correlated with increases in DENV replication [42]. Similarly, hypoxia enhances the replication and promotes a sustained infection of hepatitis C virus (HCV) by triggering alterations in liver cellular bioenergetics resulting in a higher rate of anaerobic glycolysis in a HIF-independent manner [139].
In addition, as cells adapt to a lack of oxygen, a multitude of lipids, proteins and signaling pathways are differentially expressed, which can be potentially advantageous for viral infection. For example, enhanced replication of herpes simplex virus (HSV) G207 under hypoxic conditions [2] is postulated to be due to hypoxia mediated upregulation of GADD34, which complements the replication of HSVs deficient in the viral gene γ34.5 [61]. Similarly, hypoxia enhances parvovirus B19 replication [15, 24, 118] by upregulating cellular Epo/EpoR receptor signaling in erythroid progenitor cells (EPCs) [24] which have been shown to be vital for parvovirus B19 replication [23]. This could be a contributory factor to the specificity of parvovirus B19 for infecting EPCs, which reside in the bone marrow that has oxygen concentrations of 0–4% [114].
Another virus, Kaposi’s sarcoma-associated herpesvirus (KSHV) was the first virus identified to have a functional HRE in its Rta gene. As activation of Rta results in induction of the lytic replication of the virus, this suggests that hypoxia can directly stimulate KSHV replication via HIF1α [58, 140]. Indeed, it has previously been shown that hypoxia induces the lytic replication of KSHV in primary effusion lymphoma cell lines [31].
More recently, dengue virus (DENV) infection and replication has been shown to be enhanced in monocytes at oxygen levels comparable to that within the lymph nodes (3%). This enhancement was observed both in a context of a DENV-only infection as well as antibody-dependent infection that simulates clinical secondary infection with a DENV serotype heterologous to the primary infection [52,53,54, 57]. DENV exists as 4 antigenically distinct serotypes. Antibodies produced after infection with one DENV serotype are able to enhance infection with the remaining 3 serotypes. Binding of cross-reactive or sub-neutralizing levels of antibodies to DENV enables viral entry into myeloid-derived cells via the fragment crystallizable gamma receptor (FcγR) [5, 10, 20,21,22, 26, 33, 146]. This route of infection is also commonly referred to as antibody dependent enhancement (ADE). When monocytes are incubated at 3% oxygen, HIF1α directly binds to and upregulates transcription of FcγRIIA. Moreover, hypoxia-dependent but HIF1α-independent changes in cellular membrane lipid composition further complement the increase in FcγRIIA to increase uptake of antibody-opsonized DENV. This synergistic effect is attributed to the increased proportion of ether phosphatidylethanolamine (ether-PE) in membranes of cells cultured under hypoxic conditions [46]. Taken together, such hypoxia induced changes increase myeloid cells susceptibility to antibody-dependent DENV infection. It also suggests that assessment of virus neutralizing antibodies should be conducted in myeloid cells incubated at oxygen levels that reflect the microenvironment of the lymph nodes, where these cells reside and function.
Viruses that stabilize HIF1α in an oxygen independent manner
Besides relying on the level of oxygen to modulate host cell responses via the HIF pathway, some viruses have evolved the ability to interact with components of this pathway for its benefit. Pathogens such as influenza virus [123], vaccinia virus (VACV) [100], Epstein-Barr virus (EBV) [141] and hepatitis B virus (HBV) [153] have been shown to stabilize HIF1α after infection to stimulate the transcription of hypoxia inducible genes, even under normoxic conditions (Fig. 1, Table 3).
One strategy employed by viruses to stabilize HIF is to inhibit its interaction with PHDs and VHLs (Fig. 1). VACV protein C16 stabilizes HIF1α by directly binding to PHD2 and inhibiting hydroxylation and subsequent degradation of HIF1α. This results in rapid stabilization of HIF1α early post infection activation of HIF1α response genes [100]. HIF1α is similarly stabilized during EBV infection indirectly via latent membrane protein 1 (LMP1), inducing proteasome degradation of PHD1 and 3. As a result, LMPs prevents the formation of HIF/VHL complexes which are required for HIF1a degradation [89, 141]. Importantly, as HIF1α activation induces angiogenesis, its stabilization during EBV infection may play important roles in EBV-mediated tumorigenesis and tumor progression. In another example, KSHV employs several strategies to stabilize HIF1a such as the expression of a miRNA cluster within the viral genome that binds PHD1 mRNA to downregulate its expression. In addition, the KSHV protein LANA targets VHL for degradation [14, 152]. Together, these result in the stabilization and increased activity of HIF1α during KSHV infection.
Viruses such as HCV and RSV are also known to reprogram cellular metabolism to stabilize HIF1α under normoxic conditions. Oxidative stress induced by HCV infection results in HCV-stabilized HIF1α which subsequently leads to synthesis and secretion of VEGF [109]. Similarly, RSV infection in bronchial airway epithelial cells induce the release of nitric oxide (NO), which results in HIF1α stabilization and expression of HIF1α target genes [84]. This is likely due to increased oxygen consumption via oxidative phosphorylation, which results in redistribution of intracellular oxygen away from PHDs to respiratory enzymes, so that the cell senses internal hypoxia [56].
Similarly, viruses that attenuate the VHL and HIF1a interaction results in the induction of the hypoxic response. During HBV infection, the HBV X protein (HBx) increases the expression, stabilization and transcriptional activity of HIF1α by binding to and inhibiting their interaction with VHL [68, 96, 106, 153]. In HPV infections, the oncoprotein E6 forms a complex with HIF1a to inhibit its association with VHL and thus protect HIF1a from proteasome dependent degradation [51]. This directly leads to HIF1α induced glycolysis, which contributes to the Warburg effect seen in cancer cells.
Although influenza virus naturally infects respiratory epithelial cells that are exposed to atmospheric conditions (20–21% O2 or 152–160 mmHg), recent studies suggest that H1N1 virus infection can trigger a hypoxic response. Under normoxic conditions, H1N1 influenza virus infection stabilizes HIF1α by inhibiting proteasomal activity, resulting in the activation of the HIF1α pathway [123]. Nuclear accumulation of HIF1α resulted in enhanced proinflammatory cytokines secreted from infected cells that could thus play a role in the development of severe inflammation during H1N1 infection [50].
HIF1α inhibitor as a potential anti-viral strategy
The identification of the role of HIF1α in viral infection suggests a unique opportunity for HIF1α inhibitors to be used as anti-viral drugs. HIF1α inhibitors may be effective against viral infections that have exhibited the ability to induce HIF1 α and thrive under its activity. To date, HIF1α inhibitors have been developed primarily for cancer tumor therapy. These inhibitors act on various processes [112], including HIF1α mRNA expression, protein translation, protein degradation, DNA binding and transcriptional activity (Table 4).
While an increase in mRNA expression does not necessarily equate an increase in protein expression, HIF1α mRNA levels have been suggested to be a rate-limiting factor for its translation [154]. A highly specific RNA antagonist EZN-2968 is an antisense oligonucleotide that has been shown to bind to HIF1α mRNA to reduce its translation both in vitro and in vivo. This then resulted in the reduction of HIF1α transcriptional targets [48]. Phase I clinical trials showed safety in patients and further studies are required to investigate EZN-2968 modulation of HIF1α transcriptional targets [78, 117].
To inhibit HIF1α protein translation and accumulation in cells, agents such as inhibitors of topoisomerases I and II, receptor tyrosine kinase, cyclin dependent kinases and signaling pathways are all possible candidates. As studies have shown that mTOR plays a role in HIF1α translation, inhibiting mTOR signaling could lead to downregulation of HIF1α. Indeed mTOR inhibitors such as temsirolimus [34], everolimus [138], metformin and MLN0128 [73] have all been shown to inhibit HIF1α protein translation. Stabilization of HIF1α in the cytosol requires interaction with the chaperone protein HSP90. In the presence of HSP90 inhibitors, HIF1α undergoes proteasomal degradation [74]. Therefore HSP90 inhibitors such as 17-AAG and 17-DMAG are currently in development for cancer therapy [110]. In addition, small molecules may also downregulate the activity of HIF1α by inhibiting its ability to bind to HRE and initiate transcription of target genes. Recently, a compound DJ12 was identified from a screen of 15,000 compounds to inhibit HIF1α activity by blocking its binding to HRE sequences [79]. The development of such HIF1α inhibitors provide unique and hitherto unexplored opportunities to expand our anti-viral pharmacopoeia.
Conclusion
Collectively, differences between atmospheric oxygen tensions in which in vitro experiments are generally conducted in differs drastically from that of physiological tissue oxygen microenvironments. In light of the growing body of evidence on the relationship between oxygen tensions and viral replication, the application of tissue oxygen tensions should be an important consideration when studying viral pathogenesis.
Availability of data and materials
Not applicable.
Abbreviations
- EPO:
-
Erythropoietin
- HIF:
-
Hypoxia Inducible Factor
- ARNT1:
-
Aryl hydrocarbon receptor nuclear transporter 1
- ODD:
-
Oxygen dependent degradation
- VHL:
-
Von-hippel lindeau
- PHD:
-
Prolyl hydroxylase domains
- FIH:
-
Factor inhibiting HIF
- PMK2:
-
Pyruvate kinase M2 isoform
- HRE:
-
Hypoxia response element
- HAS:
-
Hypoxia ancillary sequene
- DENV:
-
Dengue virus
- HSV:
-
Herpes simplex virus
- HIV:
-
Human immunodeficiency virus
- HCV:
-
Hepatitis C virus
- VSV:
-
Vesicular stomatitis virus
- KSHV:
-
Kaposi’s sarcoma-associated herpesvirus
- ADE:
-
Antibody dependent enhancement
- RCC:
-
Renal carcinoma cells
- VACV:
-
Vaccinia virus
- DFO:
-
Deferoxamine
References
Abrantes JL, Alves CM, Costa J, Almeida FCL, Sola-Penna M, Fontes CFL, Souza TML. Herpes simplex type 1 activates glycolysis through engagement of the enzyme 6-phosphofructo-1-kinase (PFK-1). Biochim Biophys Acta. 2012;1822:1198–206. https://doi.org/10.1016/j.bbadis.2012.04.011.
Aghi MK, Liu T-C, Rabkin S, Martuza RL. Hypoxia enhances the replication of oncolytic herpes simplex virus. Mol Ther. 2009;17:51–6. https://doi.org/10.1038/mt.2008.232.
Aprelikova O, Wood M, Tackett S, Chandramouli GVR, Barrett JC. Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection. Cancer Res. 2006;66:5641–7. https://doi.org/10.1158/0008-5472.CAN-05-3345.
Assad F, Schultheiss R, Leniger-Follert E, Wüllenweber R. Measurement of local oxygen partial pressure (PO2) of the brain cortex in cases of brain tumors. In: CNS metastases neurosurgery in the aged, advances in neurosurgery. Berlin, Heidelberg: Springer Berlin Heidelberg; 1984. p. 263–70.
Ayala-Nunez NV, Hoornweg TE, van de Pol DPI, Sjollema KA, Flipse J, van der Schaar HM, Smit JM. How antibodies alter the cell entry pathway of dengue virus particles in macrophages. Sci Rep. 2016;6:28768. https://doi.org/10.1038/srep28768.
Beppu K, Nakamura K, Linehan WM, Rapisarda A, Thiele CJ. Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells. Cancer Res. 2005;65:4775–81. https://doi.org/10.1158/0008-5472.CAN-04-3332.
Bilz NC, Jahn K, Lorenz M, Lüdtke A, Hübschen JM, Geyer H, Mankertz A, Hübner D, Liebert UG, Claus C. Rubella viruses shift cellular bioenergetics to a more oxidative and glycolytic phenotype with a strain-specific requirement for glutamine. J Virol. 2018;92:13. https://doi.org/10.1128/JVI.00934-18.
Boekstegers P, Riessen R, Seyde W. Oxygen partial pressure distribution within skeletal muscle: Indicator of whole body oxygen delivery in patients? In: Oxygen transport to tissue XII, advances in experimental medicine and biology. Boston: Springer; 1990. p. 507–14. https://doi.org/10.1007/978-1-4684-8181-5_57.
Bollinger T, Bollinger A, Gies S, Feldhoff L, Solbach W, Rupp J. Transcription regulates HIF-1|[alpha]| expression in CD4|[plus]| T cells. Immunol Cell Biol. 2016;94:109–13. https://doi.org/10.1038/icb.2015.64.
Boonnak K, Slike BM, Donofrio GC, Marovich MA. Human FcγRII cytoplasmic domains differentially influence antibody-mediated dengue virus infection. J Immunol. 2013;190:5659–65. https://doi.org/10.4049/jimmunol.1203052.
Bosco MC, Pierobon D, Blengio F, Raggi F, Vanni C, Gattorno M, Eva A, Novelli F, Cappello P, Giovarelli M, Varesio L. Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mDCs: identification of TREM-1 as a novel hypoxic marker in vitro and in vivo. Blood. 2010;117, blood–2010–06–292136–2639. https://doi.org/10.1182/blood-2010-06-292136.
Bosco MC, Puppo M, Santangelo C, Anfosso L, Pfeffer U, Fardin P, Battaglia F, Varesio L. Hypoxia modifies the transcriptome of primary human monocytes: modulation of novel immune-related genes and identification of CC-chemokine ligand 20 as a new hypoxia-inducible gene. J Immunol. 2006;177:1941–55.
Brooks AJ, Eastwood J, Beckingham IJ, Girling KJ. Liver tissue partial pressure of oxygen and carbon dioxide during partial hepatectomy. Br J Anaesth. 2004;92:735–7. https://doi.org/10.1093/bja/aeh112.
Cai QL, Knight JS, Verma SC, PLoS PZ. EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors; 2006.
Caillet-Fauquet P, Draps M-L, Di Giambattista M, de Launoit Y, Laub R. Hypoxia enables B19 erythrovirus to yield abundant infectious progeny in a pluripotent erythroid cell line. J Virol Methods. 2004;121:145–53. https://doi.org/10.1016/j.jviromet.2004.06.010.
Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, Sitkovsky MV. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol. 2001;167:6140–9.
Carreau A, Hafny Rahbi BE, Matejuk A, Grillon C, Kieda C. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med. 2011;15:1239–53. https://doi.org/10.1111/j.1582-4934.2011.01258.x.
Carrero P, Okamoto K, Coumailleau P, O'Brien S, Tanaka H, Poellinger L. Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha. Mol Cell Biol. 2000;20:402–15. https://doi.org/10.1128/MCB.20.1.402-415.2000.
Chabi S, Uzan B, Naguibneva I, Rucci J, Fahy L, Calvo J, Arcangeli M-L, Mazurier F, Pflumio F, Haddad R. Hypoxia regulates lymphoid development of human hematopoietic progenitors. Cell Rep. 2019;29:2307–2320.e6. https://doi.org/10.1016/j.celrep.2019.10.050.
Chan CYY, Low JZH, Gan ES, Ong EZ, Zhang SL-X, Tan HC, Chai X, Ghosh S, Ooi EE, Chan KR. Antibody-Dependent Dengue Virus Entry Modulates Cell Intrinsic Responses for Enhanced Infection. mSphere. 2019;4:504. https://doi.org/10.1128/mSphere.00528-19.
Chan KR, Ong EZ, Tan HC, Zhang SL-X, Zhang Q, Tang KF, Kaliaperumal N, Lim APC, Hibberd ML, Chan SH, Connolly JE, Krishnan MN, Lok SM, Hanson BJ, Lin C-N, Ooi EE. Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue. Proc Natl Acad Sci U S A. 2014;111:2722–7. https://doi.org/10.1073/pnas.1317454111.
Chawla T, Chan KR, Zhang SL, Tan HC, Lim APC, Hanson BJ, Ooi EE. Dengue virus neutralization in cells expressing fc gamma receptors. PLoS One. 2013;8:e65231. https://doi.org/10.1371/journal.pone.0065231.
Chen AY, Guan W, Lou S, Liu Z, Kleiboeker S, Qiu J. Role of erythropoietin receptor signaling in parvovirus B19 replication in human erythroid progenitor cells. J Virol. 2010;84:12385–96. https://doi.org/10.1128/JVI.01229-10.
Chen AY, Kleiboeker S, Qiu J. Productive parvovirus B19 infection of primary human erythroid progenitor cells at hypoxia is regulated by STAT5A and MEK signaling but not HIFα. PLoS Pathog. 2011;7:e1002088. https://doi.org/10.1371/journal.ppat.1002088.
Cho IR et al. Oncotropic H-1 parvovirus infection degrades HIF-1α protein in human pancreatic cancer cells independently of VHL and RACK1. Int J Oncol. 2015;46(5):2076–082.
Chotiwan N, Roehrig JT, Schlesinger JJ, Blair CD, Huang CY-H. Molecular determinants of dengue virus 2 envelope protein important for virus entry in FcγRIIA-mediated antibody-dependent enhancement of infection. Virology. 2014;456-457:238–46. https://doi.org/10.1016/j.virol.2014.03.031.
Connor JH, Naczki C, Koumenis C, Lyles DS. Replication and cytopathic effect of oncolytic vesicular stomatitis virus in hypoxic tumor cells in vitro and in vivo. J Virol. 2004;78:8960–70. https://doi.org/10.1128/JVI.78.17.8960-8970.2004.
Corcoran SE, O'Neill LAJ. HIF1α and metabolic reprogramming in inflammation. J Clin Invest. 2016;126:3699–707. https://doi.org/10.1172/JCI84431.
Cramer T, Yamanishi Y, Clausen BE, Förster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS. HIF-1α is essential for myeloid cell-mediated inflammation. Cell. 2003;112:645–57. https://doi.org/10.1016/S0092-8674(03)00154-5.
Dames SA, Martinez-Yamout M, De Guzman RN, Dyson HJ, Wright PE. Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response. PNAS. 2002;99:5271–6. https://doi.org/10.1073/pnas.082121399.
Davis DA, Rinderknecht AS, Zoeteweij JP, Aoki Y, Read-Connole EL, Tosato G, Blauvelt A, Yarchoan R. Hypoxia induces lytic replication of Kaposi sarcoma-associated herpesvirus. Blood. 2001;97:3244–50. https://doi.org/10.1182/blood.v97.10.3244.
Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM. The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1α. Cancer Res. 2006;66:3688–98. https://doi.org/10.1158/0008-5472.CAN-05-4564.
Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, Limpitikul W, Puttikhunt C, Edwards C, Duangchinda T, Supasa S, Chawansuntati K, Malasit P, Mongkolsapaya J, Screaton G. Cross-reacting antibodies enhance dengue virus infection in humans. Science. 2010;328:745–8. https://doi.org/10.1126/science.1185181.
Del Bufalo D. et al. Antiangiogenic Potential of the Mammalian Target of Rapamycin Inhibitor Temsirolimus. Cancer Res. 2006;66(11):5549–54.
Depping R, Steinhoff A, Schindler SG, Friedrich B, Fagerlund R, Metzen E, Hartmann E, Köhler M. Nuclear translocation of hypoxia-inducible factors (HIFs): involvement of the classical importin α/β pathway. Biochimica et Biophysica Acta (BBA) - Mol Cell Res. 2008;1783:394–404.
Dominguez O, Rojo P, Las Heras d S, Folgueira D, Contreras JR. Clinical presentation and characteristics of pharyngeal adenovirus infections. Pediatr Infect Dis J. 2005;24:733–4. https://doi.org/10.1097/01.inf.0000172942.96436.2d.
Ebbesen P, Toth FD, Villadsen JA, Nørskov-Lauritsen N. In vitro interferon and virus production at in vivo physiologic oxygen tensions. In Vivo. 1991;5:355–8.
Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Kuriyama YF. Molecular mechanisms of transcription activation by HLF and HIF1α in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. EMBO J. 1999;18:1905–14. https://doi.org/10.1093/emboj/18.7.1905.
Ema M, Taya S, Yokotani N. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular … , in:. Presented at the Proceedings of the …; 1997.
Fleischmann E, Kurz A, Niedermayr M, Schebesta K, Kimberger O, Sessler DI, Kabon B, Prager G. Tissue oxygenation in obese and non-obese patients during laparoscopy. Obes Surg. 2005;15:813–9. https://doi.org/10.1381/0960892054222867.
Fontaine KA, Sanchez EL, Camarda R, Lagunoff M. Dengue virus induces and requires glycolysis for optimal replication. J Virol. 2015;89:2358–66. https://doi.org/10.1128/JVI.02309-14.
Frakolaki E, Kaimou P, Moraiti M, Kalliampakou KI, Karampetsou K, Dotsika E, Liakos P, Vassilacopoulou D, Mavromara P, Bartenschlager R, Vassilaki N. The role of tissue oxygen tension in dengue virus replication. Cells. 2018;7:241. https://doi.org/10.3390/cells7120241.
Fraser IS, Baird DT, Cockburn F. Ovarian venous blood PO 2 , PCO 2 and pH in women. J Reprod Fertil. 1973;33:11–7. https://doi.org/10.1530/jrf.0.0330011.
Freedman SJ, Sun Z-YJ, Kung AL, France DS, Wagner G, Eck MJ. Structural basis for negative regulation of hypoxia-inducible factor-1|[alpha]| by CITED2. Nat Struct Mol Biol. 2003;10:504–12. https://doi.org/10.1038/nsb936.
Galbraith MD, Allen MA, Bensard CL, Wang X, Schwinn MK, Qin B, Long HW, Daniels DL, Hahn WC, Dowell RD, Espinosa JM. HIF1A employs CDK8-mediator to stimulate RNAPII elongation in response to hypoxia. Cell. 2013;153:1327–39.
Gan ES, Cheong WF, Chan KR, Ong EZ, Chai X, Tan HC, Ghosh S, Wenk MR, Ooi EE. Hypoxia enhances antibody-dependent dengue virus infection. EMBO J. 2017:e201695642. https://doi.org/10.15252/embj.201695642.
Gluckman E, Broxmeyer HA, Auerbach AD, Friedman HS, Douglas GW, Devergie A, Esperou H, Thierry D, Socie G, Lehn P. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med. 1989;321:1174–8. https://doi.org/10.1056/NEJM198910263211707.
Greenberger LM, Horak ID, Filpula D, Sapra P, Westergaard M, Frydenlund HF, Albæk C, Schrøder H, Ørum H. A RNA antagonist of hypoxia-inducible factor-1α, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther. 2008;7:3598–608. https://doi.org/10.1158/1535-7163.MCT-08-0510.
Gu YZ et al. Molecular characterization and chromosomal localization of a third α-class hypoxia inducible factor subunit, HIF3α. Gene Expr J Liver Res. 1998;7(9):205–13.
Guo X, Zhu Z, Zhang W, Meng X, Zhu Y, Han P, Zhou X, Hu Y, Wang R. Nuclear translocation of HIF-1α induced by influenza a (H1N1) infection is critical to the production of proinflammatory cytokines. Emerg Microbes Infect. 2017;6:e39–8. https://doi.org/10.1038/emi.2017.21.
Guo, Y et al. Human papillomavirus 16 E6 contributes HIF-1α induced Warburg effect by attenuating the VHL-HIF-1α interaction. Cells. 2014;15:7974–86.
Guzman MG, Alvarez M, Halstead SB. Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection. Arch Virol. 2013;158:1445–59. https://doi.org/10.1007/s00705-013-1645-3.
Guzman MG, Kouri G, MartÃnez E, Bravo J, Riverón R, Soler M, Vazquez S, Morier L. Clinical and serologic study of Cuban children with dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Bull Pan Am Health Organ. 1987;21:270–9.
Guzman MG, Kouri G, Valdes L, Bravo J, Alvarez M, Vazques S, Delgado I, Halstead SB. Epidemiologic studies on dengue in Santiago de Cuba, 1997. Am J Epidemiol. 2000;152:793–9– discussion 804. https://doi.org/10.1093/aje/152.9.793.
Habler OP, Messmer KFW. The physiology of oxygen transport. Transfus Sci. 1997;18:425–35. https://doi.org/10.1016/S0955-3886(97)00041-6.
Hagen T, Taylor CT, Lam F, Moncada S. Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1α. Science. 2003;302:1975–8. https://doi.org/10.1126/science.1088805.
Halstead SB, Nimmannitya S, Cohen SN. Observations related to pathogenesis of dengue hemorrhagic fever. IV. Relation of disease severity to antibody response and virus recovered. Yale J Biol Med. 1970;42:311–28.
Haque M, Davis DA, Wang V, Widmer I, Yarchoan R. Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) contains hypoxia response elements: relevance to lytic induction by hypoxia. J Virol. 2003;77:6761–8. https://doi.org/10.1128/JVI.77.12.6761-6768.2003.
Hara S, Hamada J, Kobayashi C, Kondo Y, Imura N. Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: suppression of HIF-mediated gene expression by HIF-3alpha. Biochem Biophys Res Commun. 2001;287:808–13. https://doi.org/10.1006/bbrc.2001.5659.
Harrison JS, Rameshwar P, Chang V, Bandari P. Oxygen saturation in the bone marrow of healthy volunteers. Blood. 2002;99:394. https://doi.org/10.1182/blood.v99.1.394.
He B, Chou J, Liebermann DA, Hoffman B, Roizman B. The carboxyl terminus of the murine MyD116 gene substitutes for the corresponding domain of the gamma (1)34.5 gene of herpes simplex virus to preclude the premature shutoff of total protein synthesis in infected human cells. J Virol. 1996;70:84–90.
Hegedus A, Kavanagh Williamson M, Huthoff H. HIV-1 pathogenicity and virion production are dependent on the metabolic phenotype of activated CD4+ T cells. Retrovirology. 2014;11:98–18. https://doi.org/10.1186/s12977-014-0098-4.
Hellwig-Bürgel T, Rutkowski K, Metzen E, Fandrey J, Jelkmann W. Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1. Blood. 1999;94:1561–7.
Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Instit. 2001;93(4):266–76.
Holland SK, Kennan RP, Schaub MM, D'Angelo MJ, Gore JC. Imaging oxygen tension in liver and spleen by 19F NMR. Magn Reson Med. 1993;29:446–58. https://doi.org/10.1002/mrm.1910290405.
Hu C-J, Wang L-Y, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003;23:9361–74. https://doi.org/10.1128/MCB.23.24.9361-9374.2003.
Hu CJ, Sataur A, Wang L, Chen H. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1α and HIF-2α. Mol Biol Cell. 2007;18:4528–42.
Hu J-L, Liu L-P, Yang S-L, Fang X, Wen L, Ren Q-G, Yu C. Hepatitis B virus induces hypoxia-inducible factor-2α expression through hepatitis B virus X protein. Oncol Rep. 2016;35:1443–8. https://doi.org/10.3892/or.2015.4480.
Hwang IIL, Watson IR, Der SD, Ohh M. Loss of VHL confers hypoxia-inducible factor (HIF)-dependent resistance to vesicular stomatitis virus: role of HIF in antiviral response. J Virol. 2006;80:10712–23. https://doi.org/10.1128/JVI.01014-06.
Hwang S, Nguyen AD, Jo Y, Engelking LJ, Brugarolas J, DeBose-Boyd RA. Hypoxia-inducible factor 1α activates insulin-induced gene 2 (Insig-2) transcription for degradation of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase in the liver. J Biol Chem. 2017;292:9382–93. https://doi.org/10.1074/jbc.M117.788562.
Imesch P, Samartzis EP, Schneider M, Fink D, Fedier A. Inhibition of transcription, expression, and secretion of the vascular epithelial growth factor in human epithelial endometriotic cells by romidepsin. Fertil Steril. 2011;95:1579–83. https://doi.org/10.1016/j.fertnstert.2010.12.058.
Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan L-J, Hammond R, Gimotty PA, Keith B, Simon MC. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 2010;120:2699–714. https://doi.org/10.1172/JCI39506.
Ingels A et al. Preclinical trial of a new dual mTOR inhibitor, MLN0128, using renal cell carcinoma tumorgrafts. Int J Cancer. 2014;134(10):2322–29.
Isaacs JS et al. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway. Journal of Biological. 2002;277:29936–44.
Jantsch J, Chakravortty D, Turza N, Prechtel AT, Buchholz B, Gerlach RG, Volke M, Gläsner J, Warnecke C, Wiesener MS, Eckardt K-U, Steinkasserer A, Hensel M, Willam C. Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function. J Immunol. 2008;180:4697–705. https://doi.org/10.4049/jimmunol.180.7.4697.
Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ. Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am J Pathol. 2000;157:2111–22. https://doi.org/10.1016/S0002-9440(10)64849-3.
Jeong J-W, Bae M-K, Ahn M-Y, Kim S-H, Sohn T-K, Bae M-H, Yoo M-A, Song EJ, Lee K-J, Kim K-W. Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell. 2002;111:709–20.
Jeong W, Rapisarda A, Park SR, Kinders RJ, Chen A, Melillo G, Turkbey B, Steinberg SM, Choyke P, Doroshow JH, Kummar S. Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors. Cancer Chemother Pharmacol. 2014;73:343–8. https://doi.org/10.1007/s00280-013-2362-z.
Jones DT, Harris AL. Identification of novel small-molecule inhibitors of hypoxia-inducible factor-1 transactivation and DNA binding. Mol Cancer Ther. 2006;5:2193–202. https://doi.org/10.1158/1535-7163.MCT-05-0443.
Jung G-S, Jeon J-H, Choi Y-K, Jang SY, Park SY, Kim S-W, Byun J-K, Kim M-K, Lee S, Shin E-C, Lee I-K, Kang YN, Park K-G. Pyruvate dehydrogenase kinase regulates hepatitis C virus replication. Sci Rep. 2016;6:30846–13. https://doi.org/10.1038/srep30846.
Kang F-W, Que L, Wu M, Wang Z-L, Sun J. Effects of trichostatin a on HIF-1α and VEGF expression in human tongue squamous cell carcinoma cells in vitro. Oncol Rep. 2012;28:193–9. https://doi.org/10.3892/or.2012.1784.
Kenneth NS, Mudie S, van Uden P, Rocha S. SWI/SNF regulates the cellular response to hypoxia. J Biol Chem. 2009;284:4123–31. https://doi.org/10.1074/jbc.M808491200.
Kessler J, Hahnel A, Wichmann H, Rot S, Kappler M, Bache M, Vordermark D. HIF-1α inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression. BMC Cancer 2008. 2010;10:605. https://doi.org/10.1186/1471-2407-10-605.
Kilani MM, Mohammed KA, Nasreen N, Tepper RS, Antony VB. RSV causes HIF-1α stabilization via NO release in primary bronchial epithelial cells. Inflammation. 2004;28:245–51.
Kim BS, Lee K, Jung HJ, Bhattarai D, Kwon HJ. HIF-1α suppressing small molecule, LW6, inhibits cancer cell growth by binding to calcineurin b homologous protein 1. Biochem Biophys Res Commun. 2015;458:14–20. https://doi.org/10.1016/j.bbrc.2015.01.031.
Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura T, D'Acquisto F, Addeo R, Makuuchi M, Esumi H. Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood. 2000;95:189–97.
Kimura H, Weisz A, Ogura T, Hitomi Y, Kurashima Y, Hashimoto K, D'Acquisto F, Makuuchi M, Esumi H. Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide. J Biol Chem. 2001;276:2292–8. https://doi.org/10.1074/jbc.M008398200.
Koh MY, Spivak-Kroizman T, Venturini S, Welsh S, Williams RR, Kirkpatrick DL, Powis G. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2008;7:90–100. https://doi.org/10.1158/1535-7163.MCT-07-0463.
Kondo S, Seo SY, Yoshizaki T, Wakisaka N, Furukawa M, Joab I, Jang KL, Pagano JS. EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1alpha through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells. Cancer Res. 2006;66:9870–7. https://doi.org/10.1158/0008-5472.CAN-06-1679.
Kraus RJ, Yu X, Cordes B-LA, Sathiamoorthi S, Iempridee T, Nawandar DM, Ma S, Romero-Masters JC, McChesney KG, Lin Z, Makielski KR, Lee DL, Lambert PF, Johannsen EC, Kenney SC, Mertz JE. Hypoxia-inducible factor-1α plays roles in Epstein-Barr virus's natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter. PLoS Pathog. 2017;13:e1006404. https://doi.org/10.1371/journal.ppat.1006404.
Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002;16:1466–71. https://doi.org/10.1101/gad.991402.
Law, R., Bukwirwa, H., 1999. The physiology of oxygen delivery. Update Anaesthesia.
Le Q-T, Chen E, Salim A, Cao H, Kong CS, Whyte R, Donington J, Cannon W, Wakelee H, Tibshirani R, Mitchell JD, Richardson D, O'Byrne KJ, Koong AC, Giaccia AJ. An evaluation of tumor oxygenation and gene expression in patients with early stage non–small cell lung cancers. Clin Cancer Res. 2006;12:1507–14. https://doi.org/10.1158/1078-0432.CCR-05-2049.
Leary TS, Klinck JR, Hayman G, Friend P, Jamieson NV, Gupta AK. Measurement of liver tissue oxygenation after orthotopic liver transplantation using a multiparameter sensor. Anaesthesia. 2002;57:1128–33. https://doi.org/10.1046/j.1365-2044.2002.02782_5.x.
Lee JS, Kim Y, Bhin J, Shin H-JR, Nam HJ, Lee SH, Yoon J-B, Binda O, Gozani O, Hwang D, Baek SH. Hypoxia-induced methylation of a pontin chromatin remodeling factor. Proc Natl Acad Sci U S A. 2011;108:13510–5. https://doi.org/10.1073/pnas.1106106108.
Liu L-P, Hu B-G, Ye C, Ho RLK, Chen GG, Lai PBS. HBx mutants differentially affect the activation of hypoxia-inducible factor-1α in hepatocellular carcinoma. Br J Cancer. 2014;110:1066–73. https://doi.org/10.1038/bjc.2013.787.
Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011;145:732–44.
Makino Y, Kanopka A, Wilson WJ, Tanaka H, Poellinger L. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus. J Biol Chem. 2002;277:32405–8. https://doi.org/10.1074/jbc.C200328200.
Maynard MA, Qi H, Chung J, Lee EHL, Kondo Y, Hara S, Conaway RC, Conaway JW, Ohh M. Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem. 2003;278:11032–40. https://doi.org/10.1074/jbc.M208681200.
Mazzon M, Peters NE, Loenarz C, Krysztofinska EM, Ember SWJ, Ferguson BJ, Smith GL. A mechanism for induction of a hypoxic response by vaccinia virus. Proc Natl Acad Sci U S A. 2013;110:12444–9. https://doi.org/10.1073/pnas.1302140110.
McNamee EN, Johnson DK, Homann D, Clambey ET. Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function. Immunol Res. 2013;55:58–70. https://doi.org/10.1007/s12026-012-8349-8.
Meixensberger J, Dings J, Kuhnigk H, Roosen K. Studies of tissue PO2 in normal and pathological human brain cortex. Acta Neurochir Suppl (Wien). 1993;59:58–63. https://doi.org/10.1007/978-3-7091-9302-0_10.
Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, Tourlomousis P, Däbritz JHM, Gottlieb E, Latorre I, Corr SC, McManus G, Ryan D, Jacobs HT, Szibor M, Xavier RJ, Braun T, Frezza C, Murphy MP, O'Neill LA. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell. 2016;167:457–470.e13. https://doi.org/10.1016/j.cell.2016.08.064.
Mimouna S, Gonçalvès D, Barnich N, Darfeuille-Michaud A, Hofman P, Vouret-Craviari V. Crohn disease-associated Escherichia coli promote gastrointestinal inflammatory disorders by activation of HIF-dependent responses. Gut Microbes. 2011;2:335–46. https://doi.org/10.4161/gmic.18771.
Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J, Ratcliffe PJ. Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem. 2009;284:16767–75. https://doi.org/10.1074/jbc.M901790200.
Moon E-J, Jeong C-H, Jeong J-W, Kim KR, Yu D-Y, Murakami S, Kim CW, Kim K-W. Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-1alpha. FASEB J. 2004;18:382–4. https://doi.org/10.1096/fj.03-0153fje.
Mottet D, Dumont V, Deccache Y, Demazy C, Ninane N, Raes M, Michiels C. Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta pathway in HepG2 cells. J Biol Chem. 2003;278:31277–85.
Muller M, Schück R, Erkens U, Sticher J, Haase C, Hempelmann G. Effects of lumbar peridural anesthesia on tissue pO2 of the large intestine in man. Anasthesiol Intensivmed Notfallmed Schmerzther. 1995;30:108–10. https://doi.org/10.1055/s-2007-996457.
Nasimuzzaman M et al. Hepatitis C virus stabilizes hypoxia-inducible factor 1α and stimulates the synthesis of vascular endothelial growth factor. J Virol. 2007;81(19):10249–57.
Neckers L. Using natural product inhibitors to validate Hsp90 as a molecular target in cancer. Curr Top Med Chem. 2006;6:1163–71.
O'Neill LAJ, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16:553–65. https://doi.org/10.1038/nri.2016.70.
Onnis B, Rapisarda A, Melillo G. Development of HIF-1 inhibitors for cancer therapy. J Cell Mol Med. 2009;13:2780–6. https://doi.org/10.1111/j.1582-4934.2009.00876.x.
Palazon A, Goldrath AW, Nizet V, Johnson RS. HIF transcription factors, inflammation, and immunity. Immunity. 2014;41:518–28. https://doi.org/10.1016/j.immuni.2014.09.008.
Parmar K, Mauch P, Vergilio J-A, Sackstein R, Down JD. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. PNAS. 2007;104:5431–6. https://doi.org/10.1073/pnas.0701152104.
Pasanen A, Heikkilä M, Rautavuoma K, Hirsilä M, Kivirikko KI, Myllyharju J. Hypoxia-inducible factor (HIF)-3α is subject to extensive alternative splicing in human tissues and cancer cells and is regulated by HIF-1 but not HIF-2. Int J Biochem Cell Biol. 2010;42:1189–200. https://doi.org/10.1016/j.biocel.2010.04.008.
Passalacqua KD, Lu J, Goodfellow I, Kolawole AO, Arche JR, Maddox RJ, Carnahan KE, O'Riordan MXD, Wobus CE. Glycolysis is an intrinsic factor for optimal replication of a Norovirus. MBio. 2019;10:609. https://doi.org/10.1128/mBio.02175-18.
Patnaik, A., Chiorean, E.G., Tolcher, A., Papadopoulos, K., Beeram, M., Kee, D., Waddell, M., Gilles, E., Buchbinder, A., 2009. EZN-2968, a novel hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) messenger ribonucleic acid (mRNA) antagonist: results of a phase I, pharmacokinetic (PK), dose-escalation study of daily administration in patients (pts) with advanced malignancies. ASCO Meeting Abstracts 27, 2564.
Pillet S, Le Guyader N, Hofer T, NguyenKhac F, Koken M, Aubin J-T, Fichelson S, Gassmann M, Morinet F. Hypoxia enhances human B19 erythrovirus gene expression in primary erythroid cells. Virology. 2004;327:1–7. https://doi.org/10.1016/j.virol.2004.06.020.
Pipiya T, Sauthoff H, Huang YQ, Chang B, Cheng J, Heitner S, Chen S, Rom WN, Hay JG. Hypoxia reduces adenoviral replication in cancer cells by downregulation of viral protein expression. Gene Ther. 2005;12:911–7. https://doi.org/10.1038/sj.gt.3302459.
Pittman RN. Regulation of tissue oxygenation. In: Colloquium Series on Integrated Systems Physiology: From Molecule to Function, vol. 3; 2011a. p. 1–100. https://doi.org/10.4199/C00029ED1V01Y201103ISP017.
Pittman RN. Oxygen gradients in the microcirculation. Acta Physiol (Oxf). 2011b;202:311–22. https://doi.org/10.1111/j.1748-1716.2010.02232.x.
Rathmell WK, Chmielecki C, Van Dyke T, Simon MC. Models of Von Hippel-Lindau tumor suppressor disease specific activity. J Clin Oncol. 2004;22:9553.
Ren L, Zhang W, Han P, Zhang J, Zhu Y, Meng X, Zhang J, Hu Y, Yi Z, Wang R. Influenza a virus (H1N1) triggers a hypoxic response by stabilizing hypoxia-inducible factor-1α via inhibition of proteasome. Virology. 2019;530:51–8. https://doi.org/10.1016/j.virol.2019.02.010.
Riedinger HJ, van Betteraey M, Probst H. Hypoxia blocks in vivo initiation of simian virus 40 replication at a stage preceding origin unwinding. J Virol. 1999;73:2243–52.
Salceda S, Caro J. Hypoxia-inducible factor 1α (HIF-1α) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions its stabilization by hypoxia depends on redox-induced changes. J Biol Chem. 1997;272:22642–7. https://doi.org/10.1074/jbc.272.36.22642.
Santos SAD, de Andrade DR. HIF-1alpha and infectious diseases: a new frontier for the development of new therapies. Rev Inst Med Trop Sao Paulo. 2017;59:e92. https://doi.org/10.1590/S1678-9946201759092.
Sapra P, Kraft P, Pastorino F, Ribatti D, Dumble M, Mehlig M, Wang M, Ponzoni M, Greenberger LM, Horak ID. Potent and sustained inhibition of HIF-1α and downstream genes by a polyethyleneglycol-SN38 conjugate, EZN-2208, results in anti-angiogenic effects. Angiogenesis. 2011;14:245–53. https://doi.org/10.1007/s10456-011-9209-1.
Schödel J, Oikonomopoulos S, Ragoussis J, Pugh CW, Ratcliffe PJ, Mole DR. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood. 2011;117:e207–17. https://doi.org/10.1182/blood-2010-10-314427.
Schurek HJ, Jost U, Baumgärtl H, Bertram H, Heckmann U. Evidence for a preglomerular oxygen diffusion shunt in rat renal cortex. Am J Phys. 1990;259:F910–5. https://doi.org/10.1152/ajprenal.1990.259.6.F910.
Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12:5447–54. https://doi.org/10.1128/MCB.12.12.5447.
Shalova IN, Lim JY, Chittezhath M, Zinkernagel AS, Beasley F, Hernández-Jiménez E, Toledano V, Cubillos-Zapata C, Rapisarda A, Chen J, Duan K, Yang H, Poidinger M, Melillo G, Nizet V, Arnalich F, López-Collazo E, Biswas SK. Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1α. Immunity. 2015;42:484–98. https://doi.org/10.1016/j.immuni.2015.02.001.
Shen BH, Hermiston TW. Effect of hypoxia on Ad5 infection, transgene expression and replication. Gene Ther. 2005;12:902–10. https://doi.org/10.1038/sj.gt.3302448.
Smallwood HS, Duan S, Morfouace M, Rezinciuc S, Shulkin BL, Shelat A, Zink EE, Milasta S, Bajracharya R, Oluwaseum AJ, Roussel MF, Green DR, Pasa-Tolic L, Thomas PG. Targeting metabolic reprogramming by influenza infection for therapeutic intervention. Cell Rep. 2017;19:1640–53. https://doi.org/10.1016/j.celrep.2017.04.039.
Thaker SK, Ch'ng J, Christofk HR. Viral hijacking of cellular metabolism. BMC Biol. 2019;17:59. https://doi.org/10.1186/s12915-019-0678-9.
Thompson AAR, Dickinson RS, Murphy F, Thomson JP, Marriott HM, Tavares A, Willson J, Williams L, Lewis A, Mirchandani A, Coelho S, Dos P, Doherty C, Ryan E, Watts E, Morton NM, Forbes S, Stimson RH, Hameed AG, Arnold N, Preston JA, Lawrie A, Finisguerra V, Mazzone M, Sadiku P, Goveia J, Taverna F, Carmeliet P, Foster SJ, Chilvers ER, Cowburn AS, Dockrell DH, Johnson RS, Meehan RR, Whyte MKB, Walmsley SR. Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism. Sci Immunol. 2017;2:eaal2861. https://doi.org/10.1126/sciimmunol.aal2861.
Tian H, McKnight SL, Russell DW. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 1997;11:72–82. https://doi.org/10.1101/gad.11.1.72.
Torre C, Perret C, Colnot S. Molecular determinants of liver zonation. Prog Mol Biol Transl Sci. 2010;97:127–50. https://doi.org/10.1016/B978-0-12-385233-5.00005-2.
Vandamme T et al. Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors. Br J Cancer. 2016;114(6):650–58.
Vassilaki N, Kalliampakou KI, Kotta-Loizou I, Befani C, Liakos P, Simos G, Mentis AF, Kalliaropoulos A, Doumba PP, Smirlis D, Foka P, Bauhofer O, Poenisch M, Windisch MP, Lee ME, Koskinas J, Bartenschlager R, Mavromara P. Low oxygen tension enhances hepatitis C virus replication. J Virol. 2013;87:2935–48. https://doi.org/10.1128/JVI.02534-12.
Veeranna RP, Haque M, Davis DA, Yang M, Yarchoan R. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen induction by hypoxia and hypoxia-inducible factors. J Virol. 2012;86:1097–108. https://doi.org/10.1128/JVI.05167-11.
Wakisaka N, Kondo S, Yoshizaki T, Murono S, Furukawa M, Pagano JS. Epstein-Barr virus latent membrane protein 1 induces synthesis of hypoxia-inducible factor 1 alpha. Mol Cell Biol. 2004;24:5223–34. https://doi.org/10.1128/MCB.24.12.5223-5234.2004.
Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N, Chilvers ER. Hypoxia-induced neutrophil survival is mediated by HIF-1α–dependent NF-κB activity. J Exp Med. 2005;201:105–15. https://doi.org/10.1084/jem.20040624.
Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. PNAS. 1995;92:5510–4.
Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995;270:1230–7. https://doi.org/10.1074/jbc.270.3.1230.
Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. PNAS. 1993;90:4304–8. https://doi.org/10.1073/pnas.90.9.4304.
Wang TT, Sewatanon J, Memoli MJ, Wrammert J, Bournazos S, Bhaumik SK, Pinsky BA, Chokephaibulkit K, Onlamoon N, Pattanapanyasat K, Taubenberger JK, Ahmed R, Ravetch JV. IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity. Science. 2017;355:395–8. https://doi.org/10.1126/science.aai8128.
Wang W, Winlove CP, Michel CC. Oxygen partial pressure in outer layers of skin of human finger nail folds. J Physiol Lond. 2003;549:855–63. https://doi.org/10.1113/jphysiol.2002.037994.
Xia X, Kung AL. Preferential binding of HIF-1 to transcriptionally active loci determines cell-type specific response to hypoxia. Genome Biol. 2009;10:R113. https://doi.org/10.1186/gb-2009-10-10-r113.
Xu D, Yao Y, Lu L, Costa M, Dai W. Plk3 functions as an essential component of the hypoxia regulatory pathway by direct phosphorylation of HIF-1alpha. J Biol Chem. 2010;285:38944–50. https://doi.org/10.1074/jbc.M110.160325.
Yamamoto M, Curiel DT. Current issues and future directions of oncolytic adenoviruses. Mol Ther. 2010;18:243–50. https://doi.org/10.1038/mt.2009.266.
Yasinska IM, Sumbayev VV. S-nitrosation of Cys-800 of HIF-1α protein activates its interaction with p300 and stimulates its transcriptional activity. FEBS Lett. 2003;549:105–9. https://doi.org/10.1016/S0014-5793(03)00807-X.
Yogev O, Lagos D, Enver T, Boshoff C. Kaposi's sarcoma herpesvirus microRNAs induce metabolic transformation of infected cells. PLoS Pathog. 2014;10(9):e1004400. https://doi.org/10.1371/journal.ppat.1004400.
Yoo Y-G, Oh SH, Park ES, Cho H, Lee N, Park H, Kim DK, Yu D-Y, Seong JK, Lee M-O. Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1alpha through activation of mitogen-activated protein kinase pathway. J Biol Chem. 2003;278:39076–84. https://doi.org/10.1074/jbc.M305101200.
Young RM, Wang SJ, Gordan JD, Ji X, Liebhaber SA, Simon MC. Hypoxia-mediated selective mRNA translation by an internal ribosome entry site-independent mechanism. J Biol Chem. 2008;283:16309–19. https://doi.org/10.1074/jbc.M710079200.
Zeng L, Zhou H-Y, Tang N-N, Zhang W-F, He G-J, Hao B, Feng Y-D, Zhu H. Wortmannin influences hypoxia-inducible factor-1 alpha expression and glycolysis in esophageal carcinoma cells. World J Gastroenterol. 2016;22:4868–80. https://doi.org/10.3748/wjg.v22.i20.4868.
Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R, Dang CV, Liu JO, Semenza GL. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc Natl Acad Sci U S A. 2008;105:19579–86. https://doi.org/10.1073/pnas.0809763105.
Zhou X, Chen J, Yi G, Deng M, Liu H, Liang M, Shi B, Fu X, Chen Y, Chen L, He Z, Wang J, Liu J. Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma. Oncotarget. 2016;7:873–84. https://doi.org/10.18632/oncotarget.6418.
Acknowledgements
Not applicable.
Funding
ESG is supported by the Estate of Tan Sri Khoo Teck Puat under its Khoo Postdoctoral Fellowship Award (Duke-NUS-KPFA/2018/0023) administered by Duke-NUS Medical School.
Author information
Authors and Affiliations
Contributions
ESG and EEO wrote the manuscript. The author(s) read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no financial or non-financial competing interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.