The CD8-Derived Chemokine XCL1/Lymphotactin Is a Conformation-Dependent, Broad-Spectrum Inhibitor of HIV-1

English version České info

CD8+ T cells play a key role in the in vivo control of HIV-1 replication via their cytolytic activity as well as their ability to secrete non-lytic soluble suppressive factors. Although the chemokines that naturally bind CCR5 (CCL3/MIP-1α, CCL4/MIP- 1β, CCL5/RANTES) are major components of the CD8-derived anti-HIV activity, evidence indicates the existence of additional, still undefined, CD8-derived HIV-suppressive factors. Here, we report the characterization of a novel anti-HIV chemokine, XCL1/lymphotactin, a member of the C-chemokine family that is produced primarily by activated CD8+ T cells and behaves as a metamorphic protein, interconverting between two structurally distinct conformations (classic and alternative). We found that XCL1 inhibits a broad spectrum of HIV-1 isolates, irrespective of their coreceptor-usage phenotype. Experiments with stabilized variants of XCL1 demonstrated that HIV-1 inhibition requires access to the alternative, all-β conformation, which interacts with proteoglycans but does not bind/activate the specific XCR1 receptor, while the classic XCL1 conformation is inactive. HIV-1 inhibition by XCL1 was shown to occur at an early stage of infection, via blockade of viral attachment and entry into host cells. Analogous to the recently described anti-HIV effect of the CXC chemokine CXCL4/PF4, XCL1-mediated inhibition is associated with direct interaction of the chemokine with the HIV-1 envelope. These results may open new perspectives for understanding the mechanisms of HIV-1 control and reveal new molecular targets for the design of effective therapeutic and preventive strategies against HIV-1.

Vyšlo v časopise: The CD8-Derived Chemokine XCL1/Lymphotactin Is a Conformation-Dependent, Broad-Spectrum Inhibitor of HIV-1. PLoS Pathog 9(12): e32767. doi:10.1371/journal.ppat.1003852
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003852

Souhrn

Zdroje

1. BrinchmannJE, GaudernackG, VartdalF (1990) CD8+ T cells inhibit HIV replication in naturally infected CD4+ T cells. Evidence for a soluble inhibitor. J Immunol 144: 2961–2966.

2. CocchiF, DeVicoAL, Garzino-DemoA, AryaSK, GalloRC, et al. (1995) Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 270: 1811–1815.

3. WalkerCM, LevyJA (1989) A diffusible lymphokine produced by CD8+ T lymphocytes suppresses HIV replication. Immunology 66: 628–630.

4. WalkerCM, MoodyDJ, StitesDP, LevyJA (1986) CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 234: 1563–1566.

5. WalkerCM, MoodyDJ, StitesDP, LevyJA (1989) CD8+ T lymphocyte control of HIV replication in cultured CD4+ cells varies among infected individuals. Cell Immunol 119: 470–475.

6. CocchiF, DeVicoAL, LuW, PopovicM, LatinovicO, et al. (2012) Soluble factors from T cells inhibiting X4 strains of HIV are a mixture of beta chemokines and RNases. Proc Natl Acad Sci U S A 109: 5411–5416.

7. DeVicoAL, GalloRC (2004) Control of HIV-1 infection by soluble factors of the immune response. Nat Rev Microbiol 2: 401–413.

8. CopelandKF, McKayPJ, RosenthalKL (1995) Suppression of activation of the human immunodeficiency virus long terminal repeat by CD8+ T cells is not lentivirus specific. AIDS Res Hum Retroviruses 11: 1321–1326.

9. MackewiczCE, BlackbournDJ, LevyJA (1995) CD8+ T cells suppress human immunodeficiency virus replication by inhibiting viral transcription. Proc Natl Acad Sci U S A 92: 2308–2312.

10. ChenCH, WeinholdKJ, BartlettJA, BolognesiDP, GreenbergML (1993) CD8+ T lymphocyte-mediated inhibition of HIV-1 long terminal repeat transcription: a novel antiviral mechanism. AIDS Res Hum Retroviruses 9: 1079–1086.

11. LehnerT, WangY, WhittallT, SeidlT (2011) Innate immunity and HIV-1 infection. Adv Dent Res 23: 19–22.

12. OlivaA, KinterAL, VaccarezzaM, RubbertA, CatanzaroA, et al. (1998) Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CC-chemokines and suppress HIV-1 entry and replication in vitro. J Clin Invest 102: 223–231.

13. KedzierskaK, CroweSM, TurvilleS, CunninghamAL (2003) The influence of cytokines, chemokines and their receptors on HIV-1 replication in monocytes and macrophages. Rev Med Virol 13: 39–56.

14. AuerbachDJ, LinY, MiaoH, CimbroR, DifioreMJ, et al. (2012) Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor. Proc Natl Acad Sci U S A 109: 9569–9574.

15. TuinstraRL, PetersonFC, KutlesaS, ElginES, KronMA, et al. (2008) Interconversion between two unrelated protein folds in the lymphotactin native state. Proc Natl Acad Sci U S A 105: 5057–5062.

16. LussoP (2006) HIV and the chemokine system: 10 years later. EMBO J 25: 447–456.

17. MullerS, DornerB, KorthauerU, MagesHW, D'ApuzzoM, et al. (1995) Cloning of ATAC, an activation-induced, chemokine-related molecule exclusively expressed in CD8+ T lymphocytes. Eur J Immunol 25: 1744–1748.

18. TikhonovI, KitabwallaM, WallaceM, MalkovskyM, VolkmanB, et al. (2001) Staphylococcal superantigens induce lymphotactin production by human CD4+ and CD8+ T cells. Cytokine 16: 73–78.

19. DerdeynCA, DeckerJM, SfakianosJN, WuX, O'BrienWA, et al. (2000) Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120. J Virol 74: 8358–8367.

20. PlattEJ, WehrlyK, KuhmannSE, ChesebroB, KabatD (1998) Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1. J Virol 72: 2855–2864.

21. WeiX, DeckerJM, LiuH, ZhangZ, AraniRB, et al. (2002) Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46: 1896–1905.

22. TuinstraRL, PetersonFC, ElginES, PelzekAJ, VolkmanBF (2007) An engineered second disulfide bond restricts lymphotactin/XCL1 to a chemokine-like conformation with XCR1 agonist activity. Biochemistry 46: 2564–2573.

23. PetersonFC, ElginES, NelsonTJ, ZhangF, HoegerTJ, et al. (2004) Identification and characterization of a glycosaminoglycan recognition element of the C chemokine lymphotactin. J Biol Chem 279: 12598–12604.

24. TrkolaA, GordonC, MatthewsJ, MaxwellE, KetasT, et al. (1999) The CC-chemokine RANTES increases the attachment of human immunodeficiency virus type 1 to target cells via glycosaminoglycans and also activates a signal transduction pathway that enhances viral infectivity. J Virol 73: 6370–6379.

25. KilbyJM, HopkinsS, VenettaTM, DiMassimoB, CloudGA, et al. (1998) Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 4: 1302–1307.

26. LeiY, TakahamaY (2012) XCL1 and XCR1 in the immune system. Microbes Infect 14: 262–267.

27. YamazakiC, MiyamotoR, HoshinoK, FukudaY, SasakiI, et al. (2010) Conservation of a chemokine system, XCR1 and its ligand, XCL1, between human and mice. Biochem Biophys Res Commun 397: 756–761.

28. GrecoG, MackewiczC, LevyJA (1999) Sensitivity of human immunodeficiency virus infection to various alpha, beta and gamma chemokines. J Gen Virol 80 (Pt 9) 2369–2373.

29. ShimizuN, TanakaA, OueA, MoriT, OhtsukiT, et al. (2009) Broad usage spectrum of G protein-coupled receptors as coreceptors by primary isolates of HIV. AIDS 23: 761–769.

30. DornerBG, DornerMB, ZhouX, OpitzC, MoraA, et al. (2009) Selective expression of the chemokine receptor XCR1 on cross-presenting dendritic cells determines cooperation with CD8+ T cells. Immunity 31: 823–833.

31. BackNK, SmitL, De JongJJ, KeulenW, SchuttenM, et al. (1994) An N-glycan within the human immunodeficiency virus type 1 gp120 V3 loop affects virus neutralization. Virology 199: 431–438.

32. GramGJ, HemmingA, BolmstedtA, JanssonB, OlofssonS, et al. (1994) Identification of an N-linked glycan in the V1-loop of HIV-1 gp120 influencing neutralization by anti-V3 antibodies and soluble CD4. Arch Virol 139: 253–261.

33. KangSM, QuanFS, HuangC, GuoL, YeL, et al. (2005) Modified HIV envelope proteins with enhanced binding to neutralizing monoclonal antibodies. Virology 331: 20–32.

34. LiY, ClevelandB, KlotsI, TravisB, RichardsonBA, et al. (2008) Removal of a single N-linked glycan in human immunodeficiency virus type 1 gp120 results in an enhanced ability to induce neutralizing antibody responses. J Virol 82: 638–651.

35. Quinones-KochsMI, BuonocoreL, RoseJK (2002) Role of N-linked glycans in a human immunodeficiency virus envelope glycoprotein: effects on protein function and the neutralizing antibody response. J Virol 76: 4199–4211.

36. ReynardF, FatmiA, VerrierB, BedinF (2004) HIV-1 acute infection env glycomutants designed from 3D model: effects on processing, antigenicity, and neutralization sensitivity. Virology 324: 90–102.

37. KwongPD, WyattR, RobinsonJ, SweetRW, SodroskiJ, et al. (1998) Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393: 648–659.

38. HonnenWJ, KrachmarovC, KaymanSC, GornyMK, Zolla-PaznerS, et al. (2007) Type-specific epitopes targeted by monoclonal antibodies with exceptionally potent neutralizing activities for selected strains of human immunodeficiency virus type 1 map to a common region of the V2 domain of gp120 and differ only at single positions from the clade B consensus sequence. J Virol 81: 1424–1432.

39. PinterA, HonnenWJ, D'AgostinoP, GornyMK, Zolla-PaznerS, et al. (2005) The C108g epitope in the V2 domain of gp120 functions as a potent neutralization target when introduced into envelope proteins derived from human immunodeficiency virus type 1 primary isolates. J Virol 79: 6909–6917.

40. WalkerLM, PhogatSK, Chan-HuiPY, WagnerD, PhungP, et al. (2009) Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326: 285–289.

41. WuZ, CocchiF, GentlesD, EricksenB, LubkowskiJ, et al. (2005) Human neutrophil alpha-defensin 4 inhibits HIV-1 infection in vitro. FEBS Lett 579: 162–166.

42. FreemanMM, SeamanMS, Rits-VollochS, HongX, KaoCY, et al. (2010) Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody. Structure 18: 1632–1641.

43. DongC, ChuaA, GangulyB, KrenskyAM, ClaybergerC (2005) Glycosylated recombinant human XCL1/lymphotactin exhibits enhanced biologic activity. J Immunol Methods 302: 136–144.

44. DorrP, WestbyM, DobbsS, GriffinP, IrvineB, et al. (2005) Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 49: 4721–4732.

45. LussoP, VangelistaL, CimbroR, SecchiM, SironiF, et al. (2011) Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity. FASEB J 25: 1230–1243.

46. VangelistaL, SecchiM, LussoP (2008) Rational design of novel HIV-1 entry inhibitors by RANTES engineering. Vaccine 26: 3008–3015.

47. YangH, RotsteinDM (2010) Novel CCR5 antagonists for the treatment of HIV infection: a review of compounds patented in 2006–2008. Expert Opin Ther Pat 20: 325–354.

48. HuangY, PaxtonWA, WolinskySM, NeumannAU, ZhangL, et al. (1996) The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med 2: 1240–1243.

49. MartinsonJJ, ChapmanNH, ReesDC, LiuYT, CleggJB (1997) Global distribution of the CCR5 gene 32-basepair deletion. Nat Genet 16: 100–103.

50. PoiesiC, De FrancescoMA, BaronioM, MancaN (2008) HIV-1 p17 binds heparan sulfate proteoglycans to activated CD4(+) T cells. Virus Res 132: 25–32.

51. BurasteroSE, FrigerioB, LopalcoL, SironiF, BredaD, et al. (2011) Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4. PLoS One 6: e22081.