Perforin Expression Directly by HIV-Specific CD8 T-Cells Is a Correlate of HIV Elite Control

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Many immune correlates of CD8⁺ T-cell-mediated control of HIV replication, including polyfunctionality, proliferative ability, and inhibitory receptor expression, have been discovered. However, no functional correlates using ex vivo cells have been identified with the known ability to cause the direct elimination of HIV-infected cells. We have recently discovered the ability of human CD8⁺ T-cells to rapidly upregulate perforin—an essential molecule for cell-mediated cytotoxicity—following antigen-specific stimulation. Here, we examined perforin expression capability in a large cross-sectional cohort of chronically HIV-infected individuals with varying levels of viral load: elite controllers (n = 35), viremic controllers (n = 29), chronic progressors (n = 27), and viremic nonprogressors (n = 6). Using polychromatic flow cytometry and standard intracellular cytokine staining assays, we measured perforin upregulation, cytokine production, and degranulation following stimulation with overlapping peptide pools encompassing all proteins of HIV. We observed that HIV-specific CD8⁺ T-cells from elite controllers consistently display an enhanced ability to express perforin directly ex vivo compared to all other groups. This ability is not restricted to protective HLA-B haplotypes, does not require proliferation or the addition of exogenous factors, is not restored by HAART, and primarily originates from effector CD8⁺ T-cells with otherwise limited functional capability. Notably, we found an inverse relationship between HIV-specific perforin expression and viral load. Thus, the capability of HIV-specific CD8⁺ T-cells to rapidly express perforin defines a novel correlate of control in HIV infection.

Vyšlo v časopise: Perforin Expression Directly by HIV-Specific CD8 T-Cells Is a Correlate of HIV Elite Control. PLoS Pathog 6(5): e32767. doi:10.1371/journal.ppat.1000917
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000917

Souhrn

Zdroje

1. LambotteO

BoufassaF

MadecY

NguyenA

GoujardC

2005 HIV controllers: a homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. Clin Infect Dis 41 1053 1056

2. LefrereJJ

MariottiM

Morand-JoubertL

ThauvinM

Roudot-ThoravalF

1999 Plasma human immunodeficiency virus RNA below 40 Copies/mL is rare in untreated persons even in the first years of infection. J Infect Dis 180 526 529

3. DeeksSG

WalkerBD

2007 Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27 406 416

4. MiguelesSA

SabbaghianMS

ShupertWL

BettinottiMP

MarincolaFM

2000 HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci U S A 97 2709 2714

5. FrahmN

KiepielaP

AdamsS

LindeCH

HewittHS

2006 Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes. Nat Immunol 7 173 178

6. HoneyborneI

PrendergastA

PereyraF

LeslieA

CrawfordH

2007 Control of human immunodeficiency virus type 1 is associated with HLA-B*13 and targeting of multiple gag-specific CD8+ T-cell epitopes. J Virol 81 3667 3672

7. EmuB

SinclairE

HatanoH

FerreA

ShacklettB

2008 HLA class I-restricted T-cell responses may contribute to the control of human immunodeficiency virus infection, but such responses are not always necessary for long-term virus control. J Virol 82 5398 5407

8. BettsMR

NasonMC

WestSM

De RosaSC

MiguelesSA

2006 HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107 4781 4789

9. BoazMJ

WatersA

MuradS

EasterbrookPJ

VyakarnamA

2002 Presence of HIV-1 Gag-specific IFN-gamma+IL-2+ and CD28+IL-2+ CD4 T cell responses is associated with nonprogression in HIV-1 infection. J Immunol 169 6376 6385

10. ZimmerliSC

HarariA

CelleraiC

VallelianF

BartPA

2005 HIV-1-specific IFN-gamma/IL-2-secreting CD8 T cells support CD4-independent proliferation of HIV-1-specific CD8 T cells. Proc Natl Acad Sci U S A 102 7239 7244

11. AlmeidaJR

PriceDA

PapagnoL

ArkoubZA

SauceD

2007 Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J Exp Med 204 2473 2485

12. HortonH

FrankI

BaydoR

JalbertE

PennJ

2006 Preservation of T cell proliferation restricted by protective HLA alleles is critical for immune control of HIV-1 infection. J Immunol 177 7406 7415

13. MiguelesSA

LaboricoAC

ShupertWL

SabbaghianMS

RabinR

2002 HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 3 1061 1068

14. Saez-CirionA

LacabaratzC

LambotteO

VersmisseP

UrrutiaA

2007 HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci U S A 104 6776 6781

15. O'ConnellKA

HanY

WilliamsTM

SilicianoRF

BlanksonJN

2009 Role of natural killer cells in a cohort of elite suppressors: low frequency of the protective KIR3DS1 allele and limited inhibition of human immunodeficiency virus type 1 replication in vitro. J Virol 83 5028 5034

16. ChenH

Piechocka-TrochaA

MiuraT

BrockmanMA

JulgBD

2009 Differential neutralization of human immunodeficiency virus (HIV) replication in autologous CD4 T cells by HIV-specific cytotoxic T lymphocytes. J Virol 83 3138 3149

17. MiguelesSA

OsborneCM

RoyceC

ComptonAA

JoshiRP

2008 Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity 29 1009 1021

18. ShiverJW

HenkartPA

1991 A noncytotoxic mast cell tumor line exhibits potent IgE-dependent cytotoxicity after transfection with the cytolysin/perforin gene. Cell 64 1175 1181

19. ShiverJW

SuL

HenkartPA

1992 Cytotoxicity with target DNA breakdown by rat basophilic leukemia cells expressing both cytolysin and granzyme A. Cell 71 315 322

20. RussellJH

LeyTJ

2002 Lymphocyte-mediated cytotoxicity. Annu Rev Immunol 20 323 370

21. MengY

HarlinH

O'KeefeJP

GajewskiTF

2006 Induction of cytotoxic granules in human memory CD8+ T cell subsets requires cell cycle progression. J Immunol 177 1981 1987

22. SandbergJK

FastNM

NixonDF

2001 Functional heterogeneity of cytokines and cytolytic effector molecules in human CD8+ T lymphocytes. J Immunol 167 181 187

23. MakedonasG

BanerjeePP

PandeyR

HerspergerAR

SanbornKB

2009 Rapid up-regulation and granule-independent transport of perforin to the immunological synapse define a novel mechanism of antigen-specific CD8+ T cell cytotoxic activity. J Immunol 182 5560 5569

24. HerspergerAR

MakedonasG

BettsMR

2008 Flow cytometric detection of perforin upregulation in human CD8 T cells. Cytometry A 73 1050 1057

25. AppayV

NixonDF

DonahoeSM

GillespieGM

DongT

2000 HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 192 63 75

26. AnderssonJ

BehbahaniH

LiebermanJ

ConnickE

LandayA

1999 Perforin is not co-expressed with granzyme A within cytotoxic granules in CD8 T lymphocytes present in lymphoid tissue during chronic HIV infection. AIDS 13 1295 1303

27. ZhangD

ShankarP

XuZ

HarnischB

ChenG

2003 Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic. Blood 101 226 235

28. BettsMR

BrenchleyJM

PriceDA

De RosaSC

DouekDC

2003 Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 281 65 78

29. Saez-CirionA

SinetM

ShinSY

UrrutiaA

VersmisseP

2009 Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses. J Immunol 182 7828 7837

30. MakedonasG

HutnickN

HaneyD

AmickAC

GardnerJ

0798 Perforin and IL-2 Upregulation Define Qualitative Differences among Highly Functional Virus-Specific Human CD8 T Cells. PLoS Pathog

31. KiepielaP

LeslieAJ

HoneyborneI

RamduthD

ThobakgaleC

2004 Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432 769 775

32. KiepielaP

NgumbelaK

ThobakgaleC

RamduthD

HoneyborneI

2007 CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 13 46 53

33. GoulderPJ

PhillipsRE

ColbertRA

McAdamS

OggG

1997 Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med 3 212 217

34. TakataH

TakiguchiM

2006 Three memory subsets of human CD8+ T cells differently expressing three cytolytic effector molecules. J Immunol 177 4330 4340

35. ChattopadhyayPK

BettsMR

PriceDA

GostickE

HortonH

2009 The cytolytic enzymes granyzme A, granzyme B, and perforin: expression patterns, cell distribution, and their relationship to cell maturity and bright CD57 expression. J Leukoc Biol 85 88 97

36. PrecopioML

BettsMR

ParrinoJ

PriceDA

GostickE

2007 Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8(+) T cell responses. J Exp Med 204 1405 1416

37. AppayV

DunbarPR

CallanM

KlenermanP

GillespieGM

2002 Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8 379 385

38. DayCL

KaufmannDE

KiepielaP

BrownJA

MoodleyES

2006 PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443 350 354

39. DayCL

KiepielaP

LeslieAJ

van der StokM

NairK

2007 Proliferative capacity of epitope-specific CD8 T-cell responses is inversely related to viral load in chronic human immunodeficiency virus type 1 infection. J Virol 81 434 438

40. HuntPW

BrenchleyJ

SinclairE

McCuneJM

RolandM

2008 Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 197 126 133

41. DeeksSG

KitchenCM

LiuL

GuoH

GasconR

2004 Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 104 942 947

42. YounesSA

Yassine-DiabB

DumontAR

BoulasselMR

GrossmanZ

2003 HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J Exp Med 198 1909 1922

43. PantaleoG

HarariA

2006 Functional signatures in antiviral T-cell immunity for monitoring virus-associated diseases. Nat Rev Immunol 6 417 423

44. BettsMR

HarariA

2008 Phenotype and function of protective T cell immune responses in HIV. Curr Opin HIV AIDS 3 349 355

45. Molleran LeeS

VillanuevaJ

SumegiJ

ZhangK

KogawaK

2004 Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet 41 137 144

46. LiebermanJ

ShankarP

ManjunathN

AnderssonJ

2001 Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection. Blood 98 1667 1677

47. HatanoH

DelwartEL

NorrisPJ

LeeTH

Dunn-WilliamsJ

2009 Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol 83 329 335

48. ShankarP

XuZ

LiebermanJ

1999 Viral-specific cytotoxic T lymphocytes lyse human immunodeficiency virus-infected primary T lymphocytes by the granule exocytosis pathway. Blood 94 3084 3093

49. FerreAL

HuntPW

CritchfieldJW

YoungDH

MorrisMM

2009 Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control. Blood 113 3978 3989

50. PipkinME

SacksJA

Cruz-GuillotyF

LichtenheldMG

BevanMJ

Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32 79 90

51. KaliaV

SarkarS

SubramaniamS

HainingWN

SmithKA

Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 32 91 103

52. HansenSG

VievilleC

WhizinN

Coyne-JohnsonL

SiessDC

2009 Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat Med 15 293 299

53. MiguelesSA

WeeksKA

NouE

BerkleyAM

RoodJE

2009 Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy. J Virol 83 11876 11889

54. PereyraF

AddoMM

KaufmannDE

LiuY

MiuraT

2008 Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis 197 563 571

55. LachenbruchPA

2001 Comparisons of two-part models with competitors. Stat Med 20 1215 1234

56. NasonM

2006 Patterns of immune response to a vaccine or virus as measured by intracellular cytokine staining in flow cytometry: hypothesis generation and comparison of groups. J Biopharm Stat 16 483 498