HIV Controller CD4+ T Cells Respond to Minimal Amounts of Gag Antigen Due to High TCR Avidity

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HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral treatment. Emerging evidence indicates that HIV control is mediated through very active cellular immune responses, though how such responses can persist over time without immune exhaustion is not yet understood. To investigate the nature of memory CD4+ T cells responsible for long-term anti-HIV responses, we characterized the growth kinetics, Vβ repertoire, and avidity for antigen of patient-derived primary CD4+ T cell lines. Specific cell lines were obtained at a high rate for both HIV controllers (16/17) and efficiently treated patients (19/20) in response to the immunodominant Gag293 peptide. However, lines from controllers showed faster growth kinetics than those of treated patients. After normalizing for growth rates, IFN-γ responses directed against the immunodominant Gag293 peptide showed higher functional avidity in HIV controllers, indicating differentiation into highly efficient effector cells. In contrast, responses to Gag161, Gag263, or CMV peptides did not differ between groups. Gag293-specific CD4+ T cells were characterized by a diverse Vβ repertoire, suggesting that multiple clones contributed to the high avidity CD4+ T cell population in controllers. The high functional avidity of the Gag293-specific response could be explained by a high avidity interaction between the TCR and the peptide-MHC complex, as demonstrated by MHC class II tetramer binding. Thus, HIV controllers harbor a pool of memory CD4+ T cells with the intrinsic ability to recognize minimal amounts of Gag antigen, which may explain how they maintain an active antiviral response in the face of very low viremia.

Vyšlo v časopise: HIV Controller CD4+ T Cells Respond to Minimal Amounts of Gag Antigen Due to High TCR Avidity. PLoS Pathog 6(2): e32767. doi:10.1371/journal.ppat.1000780
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000780

Souhrn

Zdroje

1. DeeksSG

WalkerBD

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

2. Saez-CirionA

PancinoG

SinetM

VenetA

LambotteO

2007 HIV controllers: how do they tame the virus? Trends Immunol 28 532 540

3. 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

4. ViardJP

BurgardM

HubertJB

AaronL

RabianC

2004 Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level. AIDS 18 45 49

5. SajadiMM

HerediaA

LeN

ConstantineNT

RedfieldRR

2007 HIV-1 natural viral suppressors: control of viral replication in the absence of therapy. AIDS 21 517 519

6. Saez-CirionA

LacabaratzC

LambotteO

VermisseP

UrrutiaA

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

7. 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

8. BrenchleyJM

PriceDA

SchackerTW

AsherTE

SilvestriG

2006 Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12 1365 1371

9. 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

10. PotterSJ

LacabaratzC

LambotteO

Perez-PatrigeonS

VingertB

2007 Preserved central memory and activated effector memory CD4+ T-cell subsets in human immunodeficiency virus controllers: an ANRS EP36 study. J Virol 81 13904 13915

11. PitcherCJ

QuittnerC

PetersonDM

ConnorsM

KoupRA

1999 HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med 5 518 525

12. BettsMR

NasonMC

WestSM

De RosaSC

MiguelesSA

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

13. FerreAL

HuntPW

CritchfieldJW

YoungDH

MorrisMM

2008 Mucosal immune responses to HIV-1 in elite controllers: A potential correlate of immune control. Blood 113 3978 3989

14. HarariA

DutoitV

CelleraiC

BartPA

Du PasquierRA

2006 Functional signatures of protective antiviral T-cell immunity in human virus infections. Immunol Rev 211 236 254

15. LanzavecchiaA

SallustoF

2005 Understanding the generation and function of memory T cell subsets. Curr Opin Immunol 17 326 332

16. SnyderCM

ChoKS

BonnettEL

van DommelenS

ShellamGR

2008 Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. Immunity 29 650 659

17. WoodlandDL

KohlmeierJE

2009 Migration, maintenance and recall of memory T cells in peripheral tissues. Nat Rev Immunol 9 153 161

18. OkoyeA

Meier-SchellersheimM

BrenchleyJM

HagenSI

WalkerJM

2007 Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection. J Exp Med 204 2171 2185

19. RosenbergES

BillingsleyJM

CaliendoAM

BoswellSL

SaxPE

1997 Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278 1447 1450

20. MalhotraU

HolteS

DuttaS

BerreyMM

DelpitE

2001 Role for HLA class II molecules in HIV-1 suppression and cellular immunity following antiretroviral treatment. J Clin Invest 107 505 517

21. Lubong SabadoR

KavanaghDG

KaufmannDE

FruK

BabcockE

2009 In vitro priming recapitulates in vivo HIV-1 specific T cell responses, revealing rapid loss of virus reactive CD4 T cells in acute HIV-1 infection. PLoS ONE 4 e4256 doi:10.1371/journal.pone.0004256

22. HarariA

PetitpierreS

VallelianF

PantaleoG

2004 Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy. Blood 103 966 972

23. BoritzE

PalmerBE

LivingstonB

SetteA

WilsonCC

2003 Diverse repertoire of HIV-1 p24-specific, IFN-gamma-producing CD4+ T cell clones following immune reconstitution on highly active antiretroviral therapy. J Immunol 170 1106 1116

24. 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

25. EmuB

SinclairE

FavreD

MorettoWJ

HsueP

2005 Phenotypic, functional, and kinetic parameters associated with apparent T-cell control of human immunodeficiency virus replication in individuals with and without antiretroviral treatment. J Virol 79 14169 14178

26. van GrevenyngheJ

ProcopioFA

HeZ

ChomontN

RiouC

2008 Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection. Nat Med 14 266 274

27. KaufmannDE

BaileyPM

SidneyJ

WagnerB

NorrisPJ

2004 Comprehensive analysis of human immunodeficiency virus type 1-specific CD4 responses reveals marked immunodominance of gag and nef and the presence of broadly recognized peptides. J Virol 78 4463 4477

28. YounesSA

TrautmannL

Yassine-DiabB

KalfayanLH

KernaleguenAE

2007 The duration of exposure to HIV modulates the breadth and the magnitude of HIV-specific memory CD4+ T cells. J Immunol 178 788 797

29. FonsecaSG

Coutinho-SilvaA

FonsecaLA

SeguradoAC

MoraesSL

2006 Identification of novel consensus CD4 T-cell epitopes from clade B HIV-1 whole genome that are frequently recognized by HIV-1 infected patients. AIDS 20 2263 2273

30. JonesRB

YueFY

GuXX

HunterDV

MujibS

2009 HIV-1 escapes from IL-2-producing CD4+ T cell responses without high-frequency fixation of mutations. J Virol

31. CasazzaJP

BettsMR

PriceDA

PrecopioML

RuffLE

2006 Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation. J Exp Med 203 2865 2877

32. Li PiraG

BottoneL

IvaldiF

PelizzoliR

Del GaldoF

2004 Identification of new Th peptides from the cytomegalovirus protein pp65 to design a peptide library for generation of CD4 T cell lines for cellular immunoreconstitution. Int Immunol 16 635 642

33. WiesnerM

ZentzC

HammerMH

CobboldM

KernF

2005 Selection of CMV-specific CD8+ and CD4+ T cells by mini-EBV-transformed B cell lines. Eur J Immunol 35 2110 2121

34. CharronD

1997 HLA: genetic diversity of HLA; functional and medical implications: proceedings of the Twelfth International Histocompatibility Workshop and Conference, held in Saint-Malo and Paris, June 1996: Sèvres; Paris, EDK.

35. KrogerCJ

Alexander-MillerMA

2007 Cutting edge: CD8+ T cell clones possess the potential to differentiate into both high- and low-avidity effector cells. J Immunol 179 748 751

36. WilliamsMA

RavkovEV

BevanMJ

2008 Rapid culling of the CD4+ T cell repertoire in the transition from effector to memory. Immunity 28 533 545

37. SachaJB

Giraldo-VelaJP

BuechlerMB

MartinsMA

ManessNJ

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

38. SethN

KaufmannD

LaheyT

RosenbergES

WucherpfennigKW

2005 Expansion and contraction of HIV-specific CD4 T cells with short bursts of viremia, but physical loss of the majority of these cells with sustained viral replication. J Immunol 175 6948 6958

39. 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

40. AlmeidaJR

SauceD

PriceDA

PapagnoL

ShinSY

2009 Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity. Blood 113 6351 6360

41. CastellinoF

GermainRN

2006 Cooperation between CD4+ and CD8+ T cells: when, where, and how. Annu Rev Immunol 24 519 540

42. 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

43. DzutsevAH

BelyakovIM

IsakovDV

MarguliesDH

BerzofskyJA

2007 Avidity of CD8 T cells sharpens immunodominance. Int Immunol 19 497 507

44. ZehnD

LeeSY

BevanMJ

2009 Complete but curtailed T-cell response to very low-affinity antigen. Nature 458 211 214

45. MadecY

BoufassaF

PorterK

MeyerL

2005 Spontaneous control of viral load and CD4 cell count progression among HIV-1 seroconverters. AIDS 19 2001 2007

46. ReesW

BenderJ

TeagueTK

KedlRM

CrawfordF

1999 An inverse relationship between T cell receptor affinity and antigen dose during CD4(+) T cell responses in vivo and in vitro. Proc Natl Acad of Sci U S A 96 9781 9786

47. DouekDC

BrenchleyJM

BettsMR

AmbrozakDR

HillBJ

2002 HIV preferentially infects HIV-specific CD4+ T cells. Nature 417 95 98

48. LichterfeldM

YuXG

MuiSK

WilliamsKL

TrochaA

2007 Selective depletion of high-avidity human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells after early HIV-1 infection. J Virol 81 4199 4214

49. 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

50. Alexander-MillerMA

2005 High-avidity CD8+ T cells: optimal soldiers in the war against viruses and tumors. Immunol Res 31 13 24

51. ZhaoY

BennettAD

ZhengZ

WangQJ

RobbinsPF

2007 High-affinity TCRs generated by phage display provide CD4+ T cells with the ability to recognize and kill tumor cell lines. J Immunol 179 5845 5854

52. MessaoudiI

Guevara PatinoJA

DyallR

LeMaoultJ

Nikolich-ZugichJ

2002 Direct link between mhc polymorphism, T cell avidity, and diversity in immune defense. Science 298 1797 1800

53. BelyakovIM

KuznetsovVA

KelsallB

KlinmanD

MoniuszkoM

2006 Impact of vaccine-induced mucosal high-avidity CD8+ CTLs in delay of AIDS viral dissemination from mucosa. Blood 107 3258 3264

54. NeveuB

DebeaupuisE

EchasserieauK

le Moullac-VaidyeB

GassinM

2008 Selection of high-avidity CD8 T cells correlates with control of hepatitis C virus infection. Hepatology 48 713 722

55. AhlersJD

BelyakovIM

2009 Memories that last forever: strategies for optimizing vaccine T cell memory. Blood

56. VingertB

AdoteviO

PatinD

JungS

ShrikantP

2006 The Shiga toxin B-subunit targets antigen in vivo to dendritic cells and elicits anti-tumor immunity. Eur J Immunol 36 1124 1135

57. JamesEA

BuiJ

BergerD

HustonL

RotiM

2007 Tetramer-guided epitope mapping reveals broad, individualized repertoires of tetanus toxin-specific CD4+ T cells and suggests HLA-based differences in epitope recognition. Int Immunol 19 1291 1301

58. NovakEJ

LiuAW

NepomGT

KwokWW

1999 MHC class II tetramers identify peptide-specific human CD4(+) T cells proliferating in response to influenza A antigen. J Clin Invest 104 R63 67

59. LemaitreF

ViguierM

ChoMS

FourneauJM

MaillereB

2004 Detection of low-frequency human antigen-specific CD4(+) T cells using MHC class II multimer bead sorting and immunoscope analysis. Eur J Immunol 34 2941 2949

60. WeiS

CharmleyP

RobinsonMA

ConcannonP

1994 The extent of the human germline T-cell receptor V beta gene segment repertoire. Immunogenetics 40 27 36

61. KillianMS

MonteiroJ

MatudJ

HultinLE

HausnerMA

2004 Persistent alterations in the T-cell repertoires of HIV-1-infected and at-risk uninfected men. AIDS 18 161 170

62. ThomasD