Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence

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HTLV-1 persists despite a vigorous host immune response. We found that polymorphism of HTLV-1 orf-I alter the relative amounts of the p12 precursor and its cleavage product p8, and is associated with differences in blood virus levels in humans, a correlate of disease risk. Reverse genetics in 160 HTLV-1 infected individuals demonstrated that equivalent levels of p8 and p12 are associated with high virus levels and, accordingly, genetically engineered HTLV-1s that express either predominantly p12 or p8 are poorly infectious in macaques. We found that expression of p8 is sufficient for productive infection of monocytes. Expression of either p12 alone or p8 alone is insufficient to protect infected cells from MHC-class-I restricted CTL killing. However, the balanced expression of both provides resistance of infected cells to CTL killing. Together, our findings provide the rationale to explore novel approaches to target the cleavage of the p12 protein, an essential step for viral infectivity and persistence.

Vyšlo v časopise: Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence. PLoS Pathog 10(11): e32767. doi:10.1371/journal.ppat.1004454
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004454

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1. PoieszBJ, RuscettiFW, GazdarAF, BunnPA, MinnaJD, et al. (1980) Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America 77: 7415–7419.

2. PoieszBJ, RuscettiFW, MierJW, WoodsAM, GalloRC (1980) T-cell lines established from human T-lymphocytic neoplasias by direct response to T-cell growth factor. Proc Natl Acad Sci USA 77: 6815–6819.

3. GessainA, BarinF, VernantJ-C, GoutO, MaursL, et al. (1985) Antibodies to human T-lymphotropic virus type I in patients with tropical spastic paraparesis. Lancet ii: 407–410.

4. OsameM, UsukuK, IzumoS, IjichiN, AmitaniH, et al. (1986) HTLV-I associated myelopathy, a new clinical entity. Lancet 1: 1031–1032.

5. Franchini G, Lairmore MD (2007) Human T-cell leukemia/lymphoma virus types 1 and 2. In: Fields Virology. Philadelphia LWW, editor. pp. 2071–2106.

6. AlbrechtB, D'SouzaCD, DingW, TridandapaniS, CoggeshallKM, et al. (2002) Activation of nuclear factor of activated T cells by human T-lymphotropic virus type 1 accessory protein p12(I). J Virol 76: 3493–3501.

7. KimSJ, DingW, AlbrechtB, GreenPL, LairmoreMD (2003) A conserved calcineurin-binding motif in human T lymphotropic virus type 1 p12I functions to modulate nuclear factor of activated T cell activation. J Biol Chem 278: 15550–15557.

8. NicotC, MulloyJC, FerrariMG, JohnsonJM, FuK, et al. (2001) HTLV-1 p12(I) protein enhances STAT5 activation and decreases the interleukin-2 requirement for proliferation of primary human peripheral blood mononuclear cells. Blood 98: 823–829.

9. BaiXT, NicotC (2012) Overview on HTLV-1 p12, p8, p30, p13: accomplices in persistent infection and viral pathogenesis. Front Microbiol 3: 400.

10. MulloyJC, CrowleyRW, FullenJ, LeonardWJ, FranchiniG (1996) The human T-cell leukemia/lymphotropic virus type I p12I protein binds the interleukin-2 receptor β and γc chains and affects their expression on the cell surface. Journal of Virology 70: 3599–3605.

11. BanerjeeP, FeuerG, BarkerE (2007) Human T-cell leukemia virus type 1 (HTLV-1) p12I down-modulates ICAM-1 and -2 and reduces adherence of natural killer cells, thereby protecting HTLV-1-infected primary CD4+ T cells from autologous natural killer cell-mediated cytotoxicity despite the reduction of major histocompatibility complex class I molecules on infected cells. J Virol 81: 9707–9717.

12. FukumotoR, AndresenV, BialukI, CecchinatoV, WalserJC, et al. (2009) In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein. Blood 113: 3726–3734.

13. KoralnikIJ, FullenJ, FranchiniG (1993) The p12I, p13II, and p30II proteins encoded by human T-cell leukemia/lymphotropic virus type I open reading frames I and II are localized in three different cellular compartments. Journal of Virology 67: 2360–2366.

14. FukumotoR, DundrM, NicotC, AdamsA, ValeriVW, et al. (2007) Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1. J Virol 81: 9088–9099.

15. N.VP, GoldH, AndresenV, SchwartzO, JonesK, et al. (2010) Human T-cell leukemia virus type 1 p8 protein increases cellular conduits and virus transmission. Proc Natl Acad Sci USA 107: 20738–20743.

16. EdwardsD, FukumotoR, Fau - de Castro-AmaranteMF, de Castro-AmaranteMf, Fau - AlcantaraLCJ, et al. (2014) Palmitoylation and p8-Mediated Human T-Cell Leukemia Virus Type 1 Transmission. J Virol 88: 2319–22.

17. TrovatoR, MulloyJC, JohnsonJM, TakemotoS, de OliveiraMP, et al. (1999) A Lysine-to-Arginine change found in natural alleles of the HTLV-I p12I protein greatly influences its stability. Journal of Virology 73: 6460–6467.

18. ValeriVW, HryniewiczA, AndresenV, JonesK, FeniziaC, et al. (2010) Requirement of the human T-cell leukemia virus p12 and p30 products for infectivity of human dendritic cells and macaques but not rabbits. Blood 116: 3809–3817.

19. NagaiM, YamanoY, BrennanMB, MoraCA, JacobsonS (2001) Increased HTLV-I proviral load and preferential expansion of HTLV-I Tax-specific CD8+ T cells in cerebrospinal fluid from patients with HAM/TSP. Ann Neurol 50: 807–812.

20. MatsuzakiT, NakagawaM, NagaiM, UsukuK, HiguchiI, et al. (2001) HTLV-I proviral load correlates with progression of motor disability in HAM/TSP: analysis of 239 HAM/TSP patients including 64 patients followed up for 10 years. J Neurovirol 7: 228–234.

21. YamanoY, NagaiM, BrennanM, MoraCA, SoldanSS, et al. (2002) Correlation of human T-cell lymphotropic virus type 1 (HTLV-1) mRNA with proviral DNA load, virus-specific CD8(+) T cells, and disease severity in HTLV-1-associated myelopathy (HAM/TSP). Blood 99: 88–94.

22. IwanagaM, WatanabeT, UtsunomiyaA, OkayamaA, UchimaruK, et al. (2010) Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan. Blood 116: 1211–1219.

23. Astier-GinT, PortailJP, LafondF, GuillemainB (1995) Identification of HTLV-I- or HTLV-II-producing cells by cocultivation with BHK-21 cells stably transfected with a LTR-lacZ gene construct. J Virol Methods 51: 19–29.

24. JonesKS, Petrow-SadowskiC, HuangYK, BertoletteDC, RuscettiFW (2008) Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4(+) T cells. Nat Med 14: 429–436.

25. FeniziaC, FiocchiM, JonesK, ParksRW, CeribelliM, et al. (2014) Human T-Cell Leukemia/Lymphoma Virus Type 1 p30, but Not p12/p8, Counteracts Toll-Like Receptor 3 (TLR3) and TLR4 Signaling in Human Monocytes and Dendritic Cells. J Virol 88: 393–402.

26. KoralnikI, LempJFJr, GalloRC, FranchiniG (1992) In vitro infection of human macrophages by human T-cell leukemia/lymphotropic virus type I (HTLV-I). AIDS Research and Human Retroviruses 8: 1845–1849.

27. JohnsonJM, MulloyJC, CiminaleV, FullenJ, NicotC, et al. (2000) The MHC class I heavy chain is a common target of the small proteins encoded by the 3′ end of HTLV type 1 and HTLV type 2. AIDS Research and Human Retroviruses 16: 1777–1781.

28. JohnsonJ, NicotC, FullenJ, CiminaleV, CasaretoL, et al. (2001) Free Major Histocompatibility Complex Class I Heavy Chain Is Preferentially Targeted for Degradation by Human T-Cell Leukemia/Lymphotropic Virus Type 1 p12I Protein. Journal of Virology 6086–6094.

29. KubotaR, SoldanSS, MartinR, JacobsonS (2000) An altered peptide ligand antagonizes antigen-specific T cells of patients with human T lymphotropic virus type I-associated neurological disease. J Immunol 164: 5192–5198.

30. DingW, AlbrechtB, LuoR, ZhangW, StanleyJR, et al. (2001) Endoplasmic reticulum and cis-Golgi localization of human T-lymphotropic virus type 1 p12(I): association with calreticulin and calnexin. J Virol 75: 7672–7682.

31. OkayamaA, StuverS, MatsuokaM, IshizakiJ, TanakaG, et al. (2004) Role of HTLV-1 proviral DNA load and clonality in the development of adult T-cell leukemia/lymphoma in asymptomatic carriers. Int J Cancer 110: 621–5.

32. KoyanagiY, ItoyamaY, NakamuraN, TakamatsuK, KiraJ, et al. (1993) In vivo infection of human T-cell leukemia virus type I in non-T cells. Virology 196: 25–33.

33. Enose-AkahataY, OhU, GrantC, JacobsonS (2008) Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I-associated neurologic disease. Blood 112: 2400–2410.

34. YangJ, ZhangL, YuC, YangXF, WangH (2014) Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res 2: 1.

35. FurukawaY, UsukuK, IzumoS, OsameM (2004) Human T cell lymphotropic virus type I (HTLV-I) p12I is dispensable for HTLV-I transmission and maintenance of infection in vivo. AIDS Res Hum Retroviruses 20: 1092–1099.

36. JohnsonJM, HarrodR, FranchiniG (2001) Molecular biology and pathogenesis of the human T-cell leukaemia/lymphotropic virus Type-1 (HTLV-1). Int J Exp Pathol 82: 135–147.

37. KitazonoT, OkazakiT, ArayaN, YamanoY, NakamuraT, et al. (2011) Advantage of higher-avidity CTL specific for Tax against human T-lymphotropic virus-1 infected cells and tumors. Cell Immunol 272: 11–7.

38. KannagiM, HasegawaA, TakamoriA, KinparaS, UtsunomiyaA (2012) The roles of acquired and innate immunity in human T-cell leukemia virus type 1-mediated diseases. Front Microbiol 3: 323.

39. SatouY, MatsuokaM (2010) HTLV-1 and the host immune system: how the virus disrupts immune regulation, leading to HTLV-1 associated diseases. J Clin Exp Hematop 50: 1–8.

40. CookLB, ElemansM, RowanAG, AsquithB (2013) HTLV-1: persistence and pathogenesis. Virology 435: 131–140.

41. PeaperDR, CresswellP (2008) Regulation of MHC class I assembly and peptide binding. Annu Rev Cell Dev Biol 24: 343–368.

42. FranchiniG, MulloyJC, KoralnikIJ, Lo MonicoA, SparkowskiJJ, et al. (1993) The human T-cell leukemia/lymphotropic virus type I p12I protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transformation and binds the 16-kilodalton subunit of the vacuolar H+ ATPase. Journal of Virology 67: 7701–7704.

43. AndresenV, Pise-MasisonCA, Sinha-DattaU, BellonM, ValeriV, et al. (2011) Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles. Blood 118: 1549–1559.

44. ArnoldJ, YamamotoB, LiM, PhippsAJ, YounisI, et al. (2006) Enhancement of infectivity and persistence in vivo by HBZ, a natural antisense coded protein of HTLV-1. Blood 107: 3976–3982.

45. RendeF, CavallariI, RomanelliMG, DianiE, BertazzoniU, et al. (2012) Comparison of the Genetic Organization, Expression Strategies and Oncogenic Potential of HTLV-1 and HTLV-2. Leuk Res Treatment 2012: 876153.