HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses

English version České info

In HIV, CD4+ T cells are best known as the primary targets of infection. Although emerging data has suggested a more active role in viral pathogenesis, the CD4+ T cell population remains relatively understudied. Using a novel computational approach, we predicted 29 different epitopes with mutations that potentially represent escape from CD4+ T cell responses. The predicted escaped epitopes were found to be less immunogenic than the wild type forms, suggesting that the identified escapes allow HIV to reduce its visibility to the immune system. Using longitudinal samples, we were able to show CD4+ T cells driving viral escape following acute infection. Overall, these findings significantly expand our knowledge of how CD4+ T cells can exert HIV control and influence HIV evolution, providing important implications to future vaccine development strategies.

Vyšlo v časopise: HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses. PLoS Pathog 11(8): e32767. doi:10.1371/journal.ppat.1005111
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005111

Souhrn

Zdroje

1. Goepfert PA, Lumm W, Farmer P, Matthews P, Prendergast A, et al. (2008) Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients. J Exp Med 205: 1009–1017. doi: 10.1084/jem.20072457 18426987

2. Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, et al. (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373: 117–122. 7529365

3. Watkins BA, Reitz MS Jr., Wilson CA, Aldrich K, Davis AE, et al. (1993) Immune escape by human immunodeficiency virus type 1 from neutralizing antibodies: evidence for multiple pathways. J Virol 67: 7493–7500. 7693973

4. Wei X, Decker JM, Wang S, Hui H, Kappes JC, et al. (2003) Antibody neutralization and escape by HIV-1. Nature 422: 307–312. 12646921

5. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, et al. (1997) Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 337: 734–739. 9287228

6. Borrow P, Lewicki H, Wei X, Horwitz MS, Peffer N, et al. (1997) Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med 3: 205–211. 9018240

7. Allen TM, Altfeld M, Geer SC, Kalife ET, Moore C, et al. (2005) Selective escape from CD8+ T-cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution. J Virol 79: 13239–13249. 16227247

8. Richman DD, Wrin T, Little SJ, Petropoulos CJ (2003) Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc Natl Acad Sci U S A 100: 4144–4149. 12644702

9. Alter G, Heckerman D, Schneidewind A, Fadda L, Kadie CM, et al. (2011) HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 476: 96–100. doi: 10.1038/nature10237 21814282

10. Rychert J, Saindon S, Placek S, Daskalakis D, Rosenberg E (2007) Sequence variation occurs in CD4 epitopes during early HIV infection. J Acquir Immune Defic Syndr 46: 261–267. 18167642

11. Harcourt GC, Garrard S, Davenport MP, Edwards A, Phillips RE (1998) HIV-1 variation diminishes CD4 T lymphocyte recognition. J Exp Med 188: 1785–1793. 9815256

12. Jones RB, Yue FY, Gu XX, Hunter DV, Mujib S, et al. (2009) Human immunodeficiency virus type 1 escapes from interleukin-2-producing CD4+ T-cell responses without high-frequency fixation of mutations. J Virol 83: 8722–8732. doi: 10.1128/JVI.00433-09 19553327

13. Burwitz BJ, Giraldo-Vela JP, Reed J, Newman LP, Bean AT, et al. (2012) CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller. Retrovirology 9: 91. doi: 10.1186/1742-4690-9-91 23131037

14. Soghoian DZ, Streeck H (2010) Cytolytic CD4(+) T cells in viral immunity. Expert Rev Vaccines 9: 1453–1463. doi: 10.1586/erv.10.132 21105780

15. van de Berg PJ, van Leeuwen EM, ten Berge IJ, van Lier R (2008) Cytotoxic human CD4(+) T cells. Curr Opin Immunol 20: 339–343. doi: 10.1016/j.coi.2008.03.007 18440213

16. Brown DM (2010) Cytolytic CD4 cells: Direct mediators in infectious disease and malignancy. Cell Immunol 262: 89–95. doi: 10.1016/j.cellimm.2010.02.008 20236628

17. Almeida CA, Bronke C, Roberts SG, McKinnon E, Keane NM, et al. (2011) Translation of HLA-HIV associations to the cellular level: HIV adapts to inflate CD8 T cell responses against Nef and HLA-adapted variant epitopes. J Immunol 187: 2502–2513. doi: 10.4049/jimmunol.1100691 21821798

18. Carlson JM, Brumme CJ, Martin E, Listgarten J, Brockman MA, et al. (2012) Correlates of protective cellular immunity revealed by analysis of population-level immune escape pathways in HIV-1. J Virol 86: 13202–13216. doi: 10.1128/JVI.01998-12 23055555

19. Moore CB, John M, James IR, Christiansen FT, Witt CS, et al. (2002) Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 296: 1439–1443. 12029127

20. Bhattacharya T, Daniels M, Heckerman D, Foley B, Frahm N, et al. (2007) Founder effects in the assessment of HIV polymorphisms and HLA allele associations. Science 315: 1583–1586. 17363674

21. Karosiene E, Rasmussen M, Blicher T, Lund O, Buus S, et al. (2013) NetMHCIIpan-3.0, a common pan-specific MHC class II prediction method including all three human MHC class II isotypes, HLA-DR, HLA-DP and HLA-DQ. Immunogenetics 65: 711–724. doi: 10.1007/s00251-013-0720-y 23900783

22. McKinney DM, Southwood S, Hinz D, Oseroff C, Arlehamn CS, et al. (2013) A strategy to determine HLA class II restriction broadly covering the DR, DP, and DQ allelic variants most commonly expressed in the general population. Immunogenetics 65: 357–370. doi: 10.1007/s00251-013-0684-y 23392739

23. Ranasinghe S, Cutler S, Davis I, Lu R, Soghoian DZ, et al. (2013) Association of HLA-DRB1-restricted CD4(+) T cell responses with HIV immune control. Nat Med 19: 930–933. doi: 10.1038/nm.3229 23793098

24. Addo MM, Yu XG, Rathod A, Cohen D, Eldridge RL, et al. (2003) Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J Virol 77: 2081–2092. 12525643

25. Mothe B, Llano A, Ibarrondo J, Zamarreno J, Schiaulini M, et al. (2012) CTL responses of high functional avidity and broad variant cross-reactivity are associated with HIV control. PLoS One 7: e29717. doi: 10.1371/journal.pone.0029717 22238642

26. Almeida JR, Sauce D, Price DA, Papagno L, Shin SY, et al. (2009) Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity. Blood 113: 6351–6360. doi: 10.1182/blood-2009-02-206557 19389882

27. Ranasinghe S, Flanders M, Cutler S, Soghoian DZ, Ghebremichael M, et al. (2012) HIV-specific CD4 T cell responses to different viral proteins have discordant associations with viral load and clinical outcome. J Virol 86: 277–283. doi: 10.1128/JVI.05577-11 22031937

28. Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, et al. (2008) Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A 105: 7552–7557. doi: 10.1073/pnas.0802203105 18490657

29. Goonetilleke N, Liu MK, Salazar-Gonzalez JF, Ferrari G, Giorgi E, et al. (2009) The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J Exp Med 206: 1253–1272. doi: 10.1084/jem.20090365 19487423

30. Salazar-Gonzalez JF, Salazar MG, Keele BF, Learn GH, Giorgi EE, et al. (2009) Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection. J Exp Med 206: 1273–1289. doi: 10.1084/jem.20090378 19487424

31. Owen RE, Sinclair E, Emu B, Heitman JW, Hirschkorn DF, et al. (2007) Loss of T cell responses following long-term cryopreservation. J Immunol Methods 326: 93–115. 17707394

32. Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, et al. (1997) Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278: 1447–1450. 9367954

33. Edwards BH, Bansal A, Sabbaj S, Bakari J, Mulligan MJ, et al. (2002) Magnitude of functional CD8+ T-cell responses to the gag protein of human immunodeficiency virus type 1 correlates inversely with viral load in plasma. J Virol 76: 2298–2305. 11836408

34. Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, et al. (2007) CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 13: 46–53. 17173051

35. Soghoian DZ, Jessen H, Flanders M, Sierra-Davidson K, Cutler S, et al. (2012) HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome. Sci Transl Med 4: 123ra125.

36. Koeppe JR, Campbell TB, Rapaport EL, Wilson CC (2006) HIV-1-specific CD4+ T-cell responses are not associated with significant viral epitope variation in persons with persistent plasma viremia. J Acquir Immune Defic Syndr 41: 140–148. 16394844

37. Norris PJ, Moffett HF, Yang OO, Kaufmann DE, Clark MJ, et al. (2004) Beyond help: direct effector functions of human immunodeficiency virus type 1-specific CD4(+) T cells. J Virol 78: 8844–8851. 15280492

38. Wright JK, Brumme ZL, Julg B, van der Stok M, Mncube Z, et al. (2012) Lack of association between HLA class II alleles and in vitro replication capacities of recombinant viruses encoding HIV-1 subtype C Gag-protease from chronically infected individuals. J Virol 86: 1273–1276. doi: 10.1128/JVI.06533-11 22090116

39. Goulder PJ, Phillips RE, Colbert RA, McAdam S, Ogg G, et al. (1997) Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med 3: 212–217. 9018241

40. Payne R, Muenchhoff M, Mann J, Roberts HE, Matthews P, et al. (2014) Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence. Proc Natl Acad Sci U S A 111: E5393–5400. doi: 10.1073/pnas.1413339111 25453107

41. Bansal A, Carlson J, Yan J, Akinsiku OT, Schaefer M, et al. (2010) CD8 T cell response and evolutionary pressure to HIV-1 cryptic epitopes derived from antisense transcription. J Exp Med 207: 51–59. doi: 10.1084/jem.20092060 20065064

42. Carlson JM, Brumme ZL, Rousseau CM, Brumme CJ, Matthews P, et al. (2008) Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag. PLoS Comput Biol 4: e1000225. doi: 10.1371/journal.pcbi.1000225 19023406

43. Tang J, Malhotra R, Song W, Brill I, Hu L, et al. (2010) Human leukocyte antigens and HIV type 1 viral load in early and chronic infection: predominance of evolving relationships. PLoS One 5: e9629. doi: 10.1371/journal.pone.0009629 20224785

44. Schieffer M, Jessen HK, Oster AF, Pissani F, Soghoian DZ, et al. (2014) Induction of Gag-specific CD4 T cell responses during acute HIV infection is associated with improved viral control. J Virol 88: 7357–7366. doi: 10.1128/JVI.00728-14 24741089

45. Pajewski NM, Parker SD, Poland GA, Ovsyannikova IG, Song W, et al. (2011) The role of HLA-DR-DQ haplotypes in variable antibody responses to anthrax vaccine adsorbed. Genes Immun 12: 457–465. doi: 10.1038/gene.2011.15 21368772

46. Tang J, Bansal A (2012) Protocol for analyzing human leukocyte antigen variants and sexually transmitted infections: from genotyping to immunoassays. Methods Mol Biol 903: 359–380. doi: 10.1007/978-1-61779-937-2_25 22782832

47. Guindon S, Dufayard JF, Lefort V, Anisimova M, Hordijk W, et al. (2010) New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol 59: 307–321. doi: 10.1093/sysbio/syq010 20525638

48. Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100: 9440–9445. 12883005

49. Akinsiku OT, Bansal A, Sabbaj S, Heath SL, Goepfert PA (2011) Interleukin-2 production by polyfunctional HIV-1-specific CD8 T cells is associated with enhanced viral suppression. J Acquir Immune Defic Syndr 58: 132–140. doi: 10.1097/QAI.0b013e318224d2e9 21637109

50. Bansal A, Jackson B, West K, Wang S, Lu S, et al. (2008) Multifunctional T-cell characteristics induced by a polyvalent DNA prime/protein boost human immunodeficiency virus type 1 vaccine regimen given to healthy adults are dependent on the route and dose of administration. J Virol 82: 6458–6469. doi: 10.1128/JVI.00068-08 18448544

51. Rousseau CM, Birditt BA, McKay AR, Stoddard JN, Lee TC, et al. (2006) Large-scale amplification, cloning and sequencing of near full-length HIV-1 subtype C genomes. J Virol Methods 136: 118–125. 16701907

52. Koren S, Schatz MC, Walenz BP, Martin J, Howard JT, et al. (2012) Hybrid error correction and de novo assembly of single-molecule sequencing reads. Nat Biotechnol 30: 693–700. doi: 10.1038/nbt.2280 22750884

53. Chin CS, Alexander DH, Marks P, Klammer AA, Drake J, et al. (2013) Nonhybrid, finished microbial genome assemblies from long-read SMRT sequencing data. Nat Methods 10: 563–569. doi: 10.1038/nmeth.2474 23644548

54. Ochsenbauer C, Edmonds TG, Ding H, Keele BF, Decker J, et al. (2012) Generation of transmitted/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages. J Virol 86: 2715–2728. doi: 10.1128/JVI.06157-11 22190722

55. Mailliard RB, Smith KN, Fecek RJ, Rappocciolo G, Nascimento EJ, et al. (2013) Selective induction of CTL helper rather than killer activity by natural epitope variants promotes dendritic cell-mediated HIV-1 dissemination. J Immunol 191: 2570–2580. doi: 10.4049/jimmunol.1300373 23913962

56. Sacha JB, Giraldo-Vela JP, Buechler MB, Martins MA, Maness NJ, et al. (2009) Gag- and Nef-specific CD4+ T cells recognize and inhibit SIV replication in infected macrophages early after infection. Proc Natl Acad Sci U S A 106: 9791–9796. doi: 10.1073/pnas.0813106106 19478057