A role of hypoxia-inducible factor 1 alpha in Mouse Gammaherpesvirus 68 (MHV68) lytic replication and reactivation from latency

Autoři: Darlah M. López-Rodríguez aff001;  Varvara Kirillov aff003;  Laurie T. Krug aff003;  Enrique A. Mesri aff001;  Samita Andreansky aff001
Působiště autorů: Department of Microbiology and Immunology and Miami Center for AIDS Research, Miami, Florida, United States of America aff001;  Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America aff002;  Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, United States of America aff003;  Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida aff004
Vyšlo v časopise: A role of hypoxia-inducible factor 1 alpha in Mouse Gammaherpesvirus 68 (MHV68) lytic replication and reactivation from latency. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008192
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008192


The hypoxia-inducible factor 1 alpha (HIF1α) protein and the hypoxic microenvironment are critical for infection and pathogenesis by the oncogenic gammaherpesviruses (γHV), Kaposi’ Sarcoma-associated Herpes Virus (KSHV) and Epstein-Barr virus (EBV). However, understanding the role of HIF1α during the virus life cycle and its biological relevance in the context of host pathogenesis has been challenging due to the lack of animal models for human γHV. To study the role of HIF1α, we employed the murine gammaherpesvirus 68 (MHV68), a rodent pathogen that readily infects laboratory mice. We show that MHV68 infection induces HIF1α protein and HIF1α-responsive gene expression in permissive cells. siRNA silencing or drug-inhibition of HIF1α reduce virus production due to a global downregulation of viral gene expression. Most notable was the marked decrease in many viral genes bearing hypoxia-responsive elements (HREs) such as the viral G-Protein Coupled Receptor (vGPCR), which is known to activate HIF1α transcriptional activity during KSHV infection. We found that the promoter of MHV68 ORF74 is responsive to HIF1α and MHV-68 RTA. Moreover, Intranasal infection of HIF1αLoxP/LoxP mice with MHV68 expressing Cre- recombinase impaired virus expansion during early acute infection and affected lytic reactivation in the splenocytes explanted from mice. Low oxygen concentrations accelerated lytic reactivation and enhanced virus production in MHV68 infected splenocytes. Thus, we conclude that HIF1α plays a critical role in promoting virus replication and reactivation from latency by impacting viral gene expression. Our results highlight the importance of the mutual interactions of the oxygen-sensing machinery and gammaherpesviruses in viral replication and pathogenesis.

Klíčová slova:

Herpesviruses – Hypoxia – Kaposi's sarcoma-associated herpesvirus – Mouse models – Oxygen – Viral persistence and latency – Viral replication – K cells


1. Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol. 2014 Jan;9:47–71. doi: 10.1146/annurev-pathol-012513-104720 23937437

2. Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 2002 Sep;64(5–6):993–8. doi: 10.1016/s0006-2952(02)01168-1 12213597

3. Greer SN, Metcalf JL, Wang Y, Ohh M, Ahn B, Kim H, et al. The updated biology of hypoxia-inducible factor. EMBO J. 2012 May 30;31(11):2448–60. doi: 10.1038/emboj.2012.125 22562152

4. 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 Jun;24(12):5223–34. doi: 10.1128/MCB.24.12.5223-5234.2004 15169887

5. McFarlane S, Nicholl MJ, Sutherland JS, Preston CM. Interaction of the human cytomegalovirus particle with the host cell induces hypoxia-inducible factor 1 alpha. Virology. 2011;414(1):83–90. doi: 10.1016/j.virol.2011.03.005 21481907

6. Haeberle HA, Dürrstein C, Rosenberger P, Hosakote YM, Kuhlicke J, Kempf VAJ, et al. Oxygen-independent stabilization of hypoxia inducible factor (HIF)-1 during RSV infection. PLoS One. 2008;3(10):14–6.

7. Werth N, Beerlage C, Rosenberger C, Yazdi AS, Edelmann M, Amr A, et al. Activation of hypoxia inducible factor 1 is a general phenomenon in infections with human pathogens. Ho PL, editor. PLoS One. 2010 Jan;5(7):e11576.

8. Piña-oviedo S, Khalili K, Del Valle L. Hypoxia inducible factor-1 alpha activation of the JCV promoter: role in the pathogenesis of Progressive Multifocal Leukoencephalopathy Sergio. Acta Neuropathol. 2009;118(2):235–47. doi: 10.1007/s00401-009-0533-0 19360424

9. Ren L, Zhang W, Han P, Zhang J, Zhu Y, Meng X, et al. Influenza A virus (H1N1) triggers a hypoxic response by stabilizing hypoxia-inducible factor-1α via inhibition of proteasome. Virology. 2019;530(November 2018):51–8.

10. Davis DA, Rinderknecht AS, Zoeteweij JP, Aoki Y, Read-Connole EL, Tosato G, et al. Hypoxia induces lytic replication of Kaposi sarcoma–associated herpesvirus. Blood. 2001;97(10).

11. Zhang L, Zhu C, Guo Y, Wei F, Lu J, Qin J, et al. Inhibition of KAP1 enhances hypoxia-induced KSHV reactivation through RBP-Jκ. J Virol. 2014 Apr 2;JVI.00283-14-.

12. Shrestha P, Davis DA, Veeranna RP, Carey RF, Viollet C, Yarchoan R. Hypoxia-inducible factor-1 alpha as a therapeutic target for primary effusion lymphoma. 2017;1:1–20.

13. Jiang JH, Wang N, Li A, Liao WT, Pan ZG, Mai SJ, et al. Hypoxia can contribute to the induction of the Epstein-Barr virus (EBV) lytic cycle. J Clin Virol. 2006;37(2):98–103. doi: 10.1016/j.jcv.2006.06.013 16931136

14. Kraus RJ, Yu X, Cordes BA, Sathiamoorthi S, Iempridee T, Nawandar DM, et al. Hypoxia-inducible factor-1 alpha 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(6):e1006404. doi: 10.1371/journal.ppat.1006404 28617871

15. Morinet F, Casetti L, François J-H, Capron C, Pillet S. Oxygen tension level and human viral infections. Virology. 2013;444(1):31–6.

16. Anderson LA, Lauria C, Romano N, Brown EE, Whitby D, Graubard BI, et al. Risk factors for classical Kaposi sarcoma in a population-based case-control study in Sicily. Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3435–43. doi: 10.1158/1055-9965.EPI-08-0671 19064559

17. Sobngwi E, Choukem SP, Agbalika F, Blondeau B, Fetita L-S, Lebbe C, et al. Ketosis-prone type 2 diabetes mellitus and human herpesvirus 8 infection in sub-saharan africans. JAMA. 2008 Jun 18;299(23):2770–6. doi: 10.1001/jama.299.23.2770 18560004

18. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 1994 Dec 16;266(5192):1865–9. doi: 10.1126/science.7997879 7997879

19. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995 May 4;332(18):1186–91. doi: 10.1056/NEJM199505043321802 7700311

20. Yogev O, Lagos D, Enver T, Boshoff C. Kaposi’s sarcoma herpesvirus microRNAs induce metabolic transformation of infected cells. PLoS Pathog. 2014 Sep 25;10(9):e1004400. doi: 10.1371/journal.ppat.1004400 25255370

21. Delgado T, Carroll P a, Punjabi AS, Margineantu D, Hockenbery DM, Lagunoff M. Induction of the Warburg effect by Kaposi’s sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells. Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10696–701. doi: 10.1073/pnas.1004882107 20498071

22. Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS, et al. G-protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature. 1998 Jan 1;391(6662):86–9. doi: 10.1038/34193 9422510

23. Jham BC, Ma T, Hu J, Chaisuparat R, Friedman ER, Pandolfi PP, et al. Amplification of the angiogenic signal through the activation of the TSC/mTOR/HIF axis by the KSHV vGPCR in Kaposi’s sarcoma. PLoS One. 2011 Jan;6(4):e19103. doi: 10.1371/journal.pone.0019103 21559457

24. Ma T, Patel H, Babapoor-Farrokhran S, Franklin R, Semenza GL, Sodhi A, et al. KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi’s sarcoma. Angiogenesis. 2015 Oct;18(4):477–88. doi: 10.1007/s10456-015-9475-4 26092770

25. Singh RK, Lang F, Pei Y, Jha HC, Robertson S. Metabolic reprogramming of Kaposi ‘ s sarcoma associated herpes virus infected B- cells in hypoxia. PLoS Pathog. 2018;14(5):1–28.

26. Viollet C, Davis DA, Tekeste SS, Reczko M, Ziegelbauer JM, Pezzella F, et al. RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature. PLOS Pathog. 2017;13(1):e1006143. doi: 10.1371/journal.ppat.1006143 28046107

27. Zhang L, Zhu C, Guo Y, Wei F, Lu J, Qin J, et al. Inhibition of KAP1 Enhances Hypoxia-Induced Kaposi’s Sarcoma-Associated Herpesvirus Reactivation through RBP-Jκ. J Virol. 2014 Jun 15;88(12):6873–84. doi: 10.1128/JVI.00283-14 24696491

28. Davis DA, Rinderknecht AS, Zoeteweij JP, Aoki Y, Read-Connole EL, Tosato G, et al. Hypoxia induces lytic replication of Kaposi sarcoma-associated herpesvirus. Blood. 2001 May 15;97(10):3244–50. doi: 10.1182/blood.v97.10.3244 11342455

29. Polcicova K, Hrabovska Z, Mistrikova J, Tomaskova J, Pastorek J, Pastorekova S, et al. Up-regulation of Murid herpesvirus 4 ORF50 by hypoxia: possible implication for virus reactivation from latency. Virus Res. 2008 Mar;132(1–2):257–62. doi: 10.1016/j.virusres.2007.12.004 18221814

30. Mesri E, Cesarman E, Boshoff C. Kaposi’s sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010 Oct;10(10):707–19. doi: 10.1038/nrc2888 20865011

31. Barton E, Mandal P, Speck SH. Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol. 2011 Jan;29:351–97. doi: 10.1146/annurev-immunol-072710-081639 21219186

32. Epstein ACR, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, et al. C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation. Cell. 2001 Oct 5;107:43–54. doi: 10.1016/s0092-8674(01)00507-4 11595184

33. Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber H-P, et al. Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell. 2004 Dec;6(5):485–95. doi: 10.1016/j.ccr.2004.09.026 15542432

34. Cai Q, Lan K, Verma SC, Si H, Lin D, Robertson ES. Kaposi’s sarcoma-associated herpesvirus latent protein LANA interacts with HIF-1 alpha to upregulate RTA expression during hypoxia: Latency control under low oxygen conditions. J Virol. 2006 Aug;80(16):7965–75. doi: 10.1128/JVI.00689-06 16873253

35. Carroll PA, Kenerson HL, Yeung RS, Lagunoff M. Latent Kaposi’s sarcoma-associated herpesvirus infection of endothelial cells activates hypoxia-induced factors. J Virol. 2006 Nov;80(21):10802–12. doi: 10.1128/JVI.00673-06 16956952

36. Huang Y, Lei L, Liu D, Jovin I, Russell R, Johnson RS, et al. Normal glucose uptake in the brain and heart requires an endothelial cell-specific HIF-1α-dependent function. Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17478–83. doi: 10.1073/pnas.1209281109 23047702

37. Singh RK, Lang F, Pei Y, Jha HC, Robertson ES. Metabolic reprogramming of Kaposi’s sarcoma associated herpes virus infected B- cells in hypoxia.

38. Koh MY, Spivak-kroizman T, Venturini S, Welsh S, Williams RR, Kirkpatrick DL, et al. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1 A. 2008;7(January):90–101.

39. Nathan AT, Singer M. The oxygen trail: tissue oxygenation. Br Med Bull. 1999 Jan 1;55(1):96–108. doi: 10.1258/0007142991902312 10695081

40. Moser JM, Upton JW, Allen RD, Wilson CB, Speck SH. Role of B-cell proliferation in the establishment of gammaherpesvirus latency. J Virol. 2005 Aug;79(15):9480–91. doi: 10.1128/JVI.79.15.9480-9491.2005 16014911

41. Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999 Jan;15:551–78. doi: 10.1146/annurev.cellbio.15.1.551 10611972

42. Reese TA, Wakeman BS, Choi HS, Hufford MM, Huang SC, Zhang X, et al. Helminth infection reactivates latent -herpesvirus via cytokine competition at a viral promoter. Science (80-). 2014 Jun 26;345(6196):573–7.

43. Stevenson PG, May JS, Connor V, Efstathiou S. Vaccination against a hit-and-run viral cancer. J Gen Virol. 2010 Sep;91(Pt 9):2176–85. doi: 10.1099/vir.0.023507-0 20573854

44. Dutia BM, Reid SJ, Drummond DD, Ligertwood Y, Bennet I, Rietberg W, et al. A novel Cre recombinase imaging system for tracking lymphotropic virus infection in vivo. Stevenson PG, editor. PLoS One. 2009 Jan;4(8):e6492. doi: 10.1371/journal.pone.0006492 19652715

45. Hughes DJ, Kipar A, Sample JT, Stewart JP. Pathogenesis of a Model Gammaherpesvirus in a Natural Host. J Virol. 2010;

46. Sarawar SR, Cardin RD, Brooks JW, Mehrpooya M, Tripp RA, Sarawar SR, et al. Cytokine production in the immune response to murine gammaherpesvirus 68. Cytokine Production in the Immune Response to Murine Gammaherpesvirus 68. 1996;70(5).

47. Sarawar SR, Lee BJ, Anderson M, Teng YC, Zuberi R, Von Gesjen S. Chemokine induction and leukocyte trafficking to the lungs during murine gammaherpesvirus 68 (MHV-68) infection. Virology. 2002;293(1):54–62. doi: 10.1006/viro.2001.1221 11853399

48. Bortz E, Wu TT, Patel P, Whitelegge JP, Sun R. Proteomics of bronchoalveolar lavage fluid reveals a lung oxidative stress response in murine herpesvirus-68 infection. Viruses. 2018;10(12).

49. Sunil-Chandra NP, Efstathiou S, Arno J, Nash AA. Virological and pathological features of mice infected with murine gammaherpesvirus 68. J Gen Virol. 1992;

50. Nash AA, Dutia BM, Stewart JP, Davison AJ. Natural history of murine gamma-herpesvirus infection. Philos Trans R Soc Lond B Biol Sci. 2001 Apr 29;356(1408):569–79. doi: 10.1098/rstb.2000.0779 11313012

51. Weck KE, Barkon ML, Yoo LI, Speck SH, Virgin HW I V. Mature B cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68. J Virol. 1996 Oct;70(10):6775–80. 8794315

52. Weck KE, Kim SS, Virgin HW I V, Speck SH. B cells regulate murine gammaherpesvirus 68 latency. J Virol. 1999 Jun;73(6):4651–61. 10233924

53. Cesarman E, Damania B, Krown S, Martin J, Bower M, Whitby D. Kaposi sarcoma. Nat Rev Dis Prim. 2019;681–3.

54. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, et al. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature. 2008 Jun 5;453(7196):807–11. doi: 10.1038/nature06905 18432192

55. Dong X, Feng H, Sun Q, Li H, Wu T-T, Sun R, et al. Murine gamma-herpesvirus 68 hijacks MAVS and IKKbeta to initiate lytic replication. Früh K, editor. PLoS Pathog. 2010 Jan;6(7):e1001001. doi: 10.1371/journal.ppat.1001001 20686657

56. Bottero V, Sharma-Walia N, Kerur N, Paul AG, Sadagopan S, Cannon M, et al. Kaposi Sarcoma-associated herpes virus (KSHV) G protein-coupled receptor (vGPCR) activates the ORF50 lytic switch promoter: A potential positive feedback loop for sustained ORF50 gene expression. Virology. 2009;

57. Delgado T, Carroll PA, Punjabi AS, Margineantu D, Hockenbery DM, Lagunoff M. Induction of the Warburg effect by Kaposi’s sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells. Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10696–701. doi: 10.1073/pnas.1004882107 20498071

58. Zhu Y, Ramos da Silva S, He M, Liang Q, Lu C, Feng P, et al. An Oncogenic Virus Promotes Cell Survival and Cellular Transformation by Suppressing Glycolysis. PLoS Pathog. 2016;12(5):1–27.

59. 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 Nov;80(21):10712–23. doi: 10.1128/JVI.01014-06 16928739

60. Nathan AT, Singer M. The oxygen trail: tissue oxygenation. Br Med Bull. 1999;55(1):96–108. doi: 10.1258/0007142991902312 10695081

61. Dalton-Griffin L, Wilson SJ, Kellam P. X-box binding protein 1 contributes to induction of the Kaposi’s sarcoma-associated herpesvirus lytic cycle under hypoxic conditions. J Virol. 2009;83(14):7202–9. doi: 10.1128/JVI.00076-09 19403667

62. Cummins EP, Taylor CT. Hypoxia-responsive transcription factors. Pflügers Arch. 2005;450(6):363–71. doi: 10.1007/s00424-005-1413-7 16007431

63. Davis DA. Hypoxia induces lytic replication of Kaposi sarcoma-associated herpesvirus. Blood. 2001 May 15;97(10):3244–50. doi: 10.1182/blood.v97.10.3244 11342455

64. Haque M, Wang V, Davis D a, Zheng Z-M, Yarchoan R. Genetic organization and hypoxic activation of the Kaposi’s sarcoma-associated herpesvirus ORF34-37 gene cluster. J Virol. 2006 Jul;80(14):7037–51. doi: 10.1128/JVI.00553-06 16809309

65. Sunil-Chandra NP, Arno J, Fazakerley J, Nash a a. Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68. Am J Pathol. 1994 Oct;145(4):818–26. 7943173

66. Emerling BM, Weinberg F, J-L, Mak TW, Chandel NS. PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2622–7. doi: 10.1073/pnas.0706790105 18268343

Hygiena a epidemiologie Infekční lékařství Laboratoř

Článek vyšel v časopise

PLOS Pathogens

2019 Číslo 12

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Zvyšte si kvalifikaci online z pohodlí domova

Antiseptika a prevence ve stomatologii
nový kurz
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Citikolin v neuroprotekci a neuroregeneraci: od výzkumu do klinické praxe nejen očních lékařů
Autoři: MUDr. Petr Výborný, CSc., FEBO

Zánětlivá bolest zad a axiální spondylartritida – Diagnostika a referenční strategie
Autoři: MUDr. Monika Gregová, Ph.D., MUDr. Kristýna Bubová

Diagnostika a léčba deprese pro ambulantní praxi
Autoři: MUDr. Jan Hubeňák, Ph.D

Význam nemocničního alert systému v době SARS-CoV-2
Autoři: doc. MUDr. Helena Lahoda Brodská, Ph.D., prim. MUDr. Václava Adámková

Všechny kurzy
Kurzy Doporučená témata Časopisy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se