#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

The Expression of Functional Vpx during Pathogenic SIVmac Infections of Rhesus Macaques Suppresses SAMHD1 in CD4 Memory T Cells


Primate lentiviruses, such as HIV and its SIV simian relative, encode accessory proteins that suppress cellular restriction factors interfering with efficient replication. One of these, designated Vpx, is produced in infected cells by HIV-2 and some SIV strains, which cause endemic infections in African monkeys. The primary function of Vpx has long been thought to facilitate infectivity in dendritic cells and macrophage by degrading the Sterile Alpha Motif and HD domain-containing protein 1 (SAMHD1), which restricts virus replication in these cells. Using SIVmac carrying a mutated Vpx gene with a single amino acid change that prevents it from binding to DCAF1 and subsequently mediating the degradation of SAMHD1, we show that virus infection of CD4+ T lymphocytes is markedly compromised both in vitro and in vivo. The SIV Vpx mutant is severely attenuated in establishing new infections in inoculated rhesus monkeys, in producing high levels of virus progeny, in degrading SAMHD1 in memory CD4+ T cell in infected animals, and in inducing symptomatic disease. Thus, although once considered to be only critical for optimal replication in macrophage based on earlier studies performed with cultured cells, the SIV Vpx protein is functionally important in vivo for establishing the primary infection in rhesus macaques, sustaining high levels of virus replication in CD4+ T lymphocytes, and promoting the onset of symptomatic immunodeficiency.


Vyšlo v časopise: The Expression of Functional Vpx during Pathogenic SIVmac Infections of Rhesus Macaques Suppresses SAMHD1 in CD4 Memory T Cells. PLoS Pathog 11(5): e32767. doi:10.1371/journal.ppat.1004928
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004928

Souhrn

Primate lentiviruses, such as HIV and its SIV simian relative, encode accessory proteins that suppress cellular restriction factors interfering with efficient replication. One of these, designated Vpx, is produced in infected cells by HIV-2 and some SIV strains, which cause endemic infections in African monkeys. The primary function of Vpx has long been thought to facilitate infectivity in dendritic cells and macrophage by degrading the Sterile Alpha Motif and HD domain-containing protein 1 (SAMHD1), which restricts virus replication in these cells. Using SIVmac carrying a mutated Vpx gene with a single amino acid change that prevents it from binding to DCAF1 and subsequently mediating the degradation of SAMHD1, we show that virus infection of CD4+ T lymphocytes is markedly compromised both in vitro and in vivo. The SIV Vpx mutant is severely attenuated in establishing new infections in inoculated rhesus monkeys, in producing high levels of virus progeny, in degrading SAMHD1 in memory CD4+ T cell in infected animals, and in inducing symptomatic disease. Thus, although once considered to be only critical for optimal replication in macrophage based on earlier studies performed with cultured cells, the SIV Vpx protein is functionally important in vivo for establishing the primary infection in rhesus macaques, sustaining high levels of virus replication in CD4+ T lymphocytes, and promoting the onset of symptomatic immunodeficiency.


Zdroje

1. Beer BE, Foley BT, Kuiken CL, Tooze Z, Goeken RM, Brown CR, et al. Characterization of novel simian immunodeficiency viruses from red-capped mangabeys from Nigeria (SIVrcmNG409 and-NG411). J Virol. 2001;75(24):12014–27. 11711592

2. Henderson LE, Sowder RC, Copeland TD, Benveniste RE, Oroszlan S. Isolation and characterization of a novel protein (X-ORF product) from SIV and HIV-2. Science. 1988;241(4862):199–201. 3388031

3. Hu J, Switzer WM, Foley BT, Robertson DL, Goeken RM, Korber BT, et al. Characterization and comparison of recombinant simian immunodeficiency virus from drill (Mandrillus leucophaeus) and mandrill (Mandrillus sphinx) isolates. J Virol. 2003;77(8):4867–80. 12663793

4. Yu XF, Ito S, Essex M, Lee TH. A naturally immunogenic virion-associated protein specific for HIV-2 and SIV. Nature. 1988;335(6187):262–5. 2842694

5. Baldauf HM, Pan X, Erikson E, Schmidt S, Daddacha W, Burggraf M, et al. SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells. Nat Med. 2012;18(11):1682–7. doi: 10.1038/nm.2964 22972397

6. Descours B, Cribier A, Chable-Bessia C, Ayinde D, Rice G, Crow Y, et al. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4(+) T-cells. Retrovirology. 2012;9:87. doi: 10.1186/1742-4690-9-87 23092122

7. Hrecka K, Hao C, Gierszewska M, Swanson SK, Kesik-Brodacka M, Srivastava S, et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature. 2011;474(7353):658–61. doi: 10.1038/nature10195 21720370

8. Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C, Segeral E, et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature. 2011;474(7353):654–7. doi: 10.1038/nature10117 21613998

9. Gibbs JS, Regier DA, Desrosiers RC. Construction and in vitro properties of SIVmac mutants with deletions in "nonessential" genes. AIDS Res Hum Retroviruses. 1994;10(5):607–16. 7917522

10. Hirsch VM, Sharkey ME, Brown CR, Brichacek B, Goldstein S, Wakefield J, et al. Vpx is required for dissemination and pathogenesis of SIV(SM) PBj: evidence of macrophage-dependent viral amplification. Nat Med. 1998;4(12):1401–8. 9846578

11. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature. 2005;434(7037):1093–7. 15793563

12. Nishimura Y, Brown CR, Mattapallil JJ, Igarashi T, Buckler-White A, Lafont BA, et al. Resting naive CD4+ T cells are massively infected and eliminated by X4-tropic simian-human immunodeficiency viruses in macaques. Proc Natl Acad Sci U S A. 2005;102(22):8000–5. 15911767

13. Zhang Z, Schuler T, Zupancic M, Wietgrefe S, Staskus KA, Reimann KA, et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science. 1999;286(5443):1353–7. 10558989

14. Guyader M, Emerman M, Montagnier L, Peden K. VPX mutants of HIV-2 are infectious in established cell lines but display a severe defect in peripheral blood lymphocytes. EMBO J. 1989;8(4):1169–75. Epub 1989/04/01. 2743977

15. Kappes JC, Conway JA, Lee SW, Shaw GM, Hahn BH. Human immunodeficiency virus type 2 vpx protein augments viral infectivity. Virology. 1991;184(1):197–209. Epub 1991/09/01. 1714662

16. Bergamaschi A, Ayinde D, David A, Le Rouzic E, Morel M, Collin G, et al. The human immunodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1 DCAF1 ubiquitin ligase to overcome a postentry block in macrophage infection. J Virol. 2009;83(10):4854–60. doi: 10.1128/JVI.00187-09 19264781

17. Schwefel D, Groom HC, Boucherit VC, Christodoulou E, Walker PA, Stoye JP, et al. Structural basis of lentiviral subversion of a cellular protein degradation pathway. Nature. 2014;505(7482):234–8. doi: 10.1038/nature12815 24336198

18. Srivastava S, Swanson SK, Manel N, Florens L, Washburn MP, Skowronski J. Lentiviral Vpx accessory factor targets VprBP/DCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligase to enable macrophage infection. PLoS Pathog. 2008;4(5):e1000059. doi: 10.1371/journal.ppat.1000059 18464893

19. Cribier A, Descours B, Valadao AL, Laguette N, Benkirane M. Phosphorylation of SAMHD1 by cyclin A2/CDK1 regulates its restriction activity toward HIV-1. Cell Rep. 2013;3(4):1036–43. doi: 10.1016/j.celrep.2013.03.017 23602554

20. Welbourn S, Dutta SM, Semmes OJ, Strebel K. Restriction of virus infection but not catalytic dNTPase activity is regulated by phosphorylation of SAMHD1. J Virol. 2013;87(21):11516–24. doi: 10.1128/JVI.01642-13 23966382

21. White TE, Brandariz-Nunez A, Valle-Casuso JC, Amie S, Nguyen LA, Kim B, et al. The retroviral restriction ability of SAMHD1, but not its deoxynucleotide triphosphohydrolase activity, is regulated by phosphorylation. Cell Host Microbe. 2013;13(4):441–51. Epub 2013/04/23. doi: 10.1016/j.chom.2013.03.005 23601106

22. Brenchley JM, Hill BJ, Ambrozak DR, Price DA, Guenaga FJ, Casazza JP, et al. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol. 2004;78(3):1160–8. Epub 2004/01/15. 14722271

23. Picker LJ, Hagen SI, Lum R, Reed-Inderbitzin EF, Daly LM, Sylwester AW, et al. Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J Exp Med. 2004;200(10):1299–314. Epub 2004/11/17. 15545355

24. Nishimura Y, Igarashi T, Buckler-White A, Buckler C, Imamichi H, Goeken RM, et al. Loss of naive cells accompanies memory CD4+ T-cell depletion during long-term progression to AIDS in Simian immunodeficiency virus-infected macaques. J Virol. 2007;81(2):893–902. 17093193

25. Belshan M, Mahnke LA, Ratner L. Conserved amino acids of the human immunodeficiency virus type 2 Vpx nuclear localization signal are critical for nuclear targeting of the viral preintegration complex in non-dividing cells. Virology. 2006;346(1):118–26. 16325220

26. Fletcher TM 3rd, Brichacek B, Sharova N, Newman MA, Stivahtis G, Sharp PM, et al. Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIV(SM). EMBO J. 1996;15(22):6155–65. 8947037

27. Gibbs JS, Lackner AA, Lang SM, Simon MA, Sehgal PK, Daniel MD, et al. Progression to AIDS in the absence of a gene for vpr or vpx. Journal of virology. 1995;69(4):2378–83. 7884883

28. Wei W, Guo H, Han X, Liu X, Zhou X, Zhang W, et al. A novel DCAF1-binding motif required for Vpx-mediated degradation of nuclear SAMHD1 and Vpr-induced G2 arrest. Cell Microbiol. 2012;14(11):1745–56. doi: 10.1111/j.1462-5822.2012.01835.x 22776683

29. Belshan M, Kimata JT, Brown C, Cheng X, McCulley A, Larsen A, et al. Vpx is critical for SIVmne infection of pigtail macaques. Retrovirology. 2012;9:32. Epub 2012/04/26. doi: 10.1186/1742-4690-9-32 22531456

30. Cheng X, Ratner L. HIV-2 Vpx protein interacts with interferon regulatory factor 5 (IRF5) and inhibits its function. J Biol Chem. 2014;289(13):9146–57. Epub 2014/02/18. doi: 10.1074/jbc.M113.534321 24532789

31. Fujita M, Nomaguchi M, Adachi A, Otsuka M. SAMHD1-Dependent and-Independent Functions of HIV-2/SIV Vpx Protein. Front Microbiol. 2012;3:297. Epub 2012/08/22. doi: 10.3389/fmicb.2012.00297 22908011

32. Reinhard C, Bottinelli D, Kim B, Luban J. Vpx rescue of HIV-1 from the antiviral state in mature dendritic cells is independent of the intracellular deoxynucleotide concentration. Retrovirology. 2014;11:12. Epub 2014/02/04. doi: 10.1186/1742-4690-11-12 24485168

33. Klatt NR, Canary LA, Vanderford TH, Vinton CL, Engram JC, Dunham RM, et al. Dynamics of simian immunodeficiency virus SIVmac239 infection in pigtail macaques. Journal of virology. 2012;86(2):1203–13. Epub 2011/11/18. doi: 10.1128/JVI.06033-11 22090099

34. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004;200(6):749–59. 15365096

35. Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998;280(5362):427–31. 9545219

36. Estes J, Baker JV, Brenchley JM, Khoruts A, Barthold JL, Bantle A, et al. Collagen deposition limits immune reconstitution in the gut. J Infect Dis. 2008;198(4):456–64. Epub 2008/07/05. doi: 10.1086/590112 18598193

37. Mehandru S, Poles MA, Tenner-Racz K, Jean-Pierre P, Manuelli V, Lopez P, et al. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS Med. 2006;3(12):e484. Epub 2006/12/07. 17147468

38. Westmoreland SV, Converse AP, Hrecka K, Hurley M, Knight H, Piatak M, et al. SIV vpx is essential for macrophage infection but not for development of AIDS. PLoS One. 2014;9(1):e84463. doi: 10.1371/journal.pone.0084463 24465411

39. Amie SM, Noble E, Kim B. Intracellular nucleotide levels and the control of retroviral infections. Virology. 2013;436(2):247–54. doi: 10.1016/j.virol.2012.11.010 23260109

40. Endo Y, Igarashi T, Nishimura Y, Buckler C, Buckler-White A, Plishka R, et al. Short- and long-term clinical outcomes in rhesus monkeys inoculated with a highly pathogenic chimeric simian/human immunodeficiency virus. J Virol. 2000;74(15):6935–45. 10888632

41. Nishimura Y, Igarashi T, Donau OK, Buckler-White A, Buckler C, Lafont BA, et al. Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses. Proc Natl Acad Sci U S A. 2004;101(33):12324–9. Epub 2004/08/07. 15297611

42. Salazar-Gonzalez JF, Bailes E, Pham KT, Salazar MG, Guffey MB, Keele BF, et al. Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing. J Virol. 2008;82(8):3952–70. doi: 10.1128/JVI.02660-07 18256145

43. Imamichi H, Igarashi T, Imamichi T, Donau OK, Endo Y, Nishimura Y, et al. Amino acid deletions are introduced into the V2 region of gp120 during independent pathogenic simian immunodeficiency virus/HIV chimeric virus (SHIV) infections of rhesus monkeys generating variants that are macrophage tropic. Proc Natl Acad Sci U S A. 2002;99(21):13813–8. 12370415

44. Nishimura Y, Shingai M, Willey R, Sadjadpour R, Lee WR, Brown CR, et al. Generation of the pathogenic R5-tropic simian/human immunodeficiency virus SHIVAD8 by serial passaging in rhesus macaques. J Virol. 2010;84(9):4769–81. Epub 2010/02/12. doi: 10.1128/JVI.02279-09 20147396

45. Willey RL, Smith DH, Lasky LA, Theodore TS, Earl PL, Moss B, et al. In vitro mutagenesis identifies a region within the envelope gene of the human immunodeficiency virus that is critical for infectivity. J Virol. 1988;62(1):139–47. 3257102

46. O'Doherty U, Swiggard WJ, Malim MH. Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding. J Virol. 2000;74(21):10074–80. 11024136

47. Yee JK, Miyanohara A, LaPorte P, Bouic K, Burns JC, Friedmann T. A general method for the generation of high-titer, pantropic retroviral vectors: highly efficient infection of primary hepatocytes. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(20):9564–8. 7937806

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2015 Číslo 5
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#