#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

CD8+ Lymphocytes Control Viral Replication in SIVmac239-Infected Rhesus Macaques without Decreasing the Lifespan of Productively Infected Cells


While CD8+ T cells are clearly important in controlling virus replication during HIV and SIV infections, the mechanisms underlying this antiviral effect remain poorly understood. In this study, we assessed the in vivo effect of CD8+ lymphocyte depletion on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques. We treated two groups of animals that were either CD8+ lymphocyte-depleted or controls with antiretroviral therapy, and used mathematical modeling to assess the lifespan of infected cells either in the presence or absence of CD8+ lymphocytes. We found that, in both early (day 57 post-SIV) and late (day 177 post-SIV) chronic SIV infection, depletion of CD8+ lymphocytes did not result in a measurable increase in the lifespan of either short- or long-lived productively infected cells in vivo. This result indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication.


Vyšlo v časopise: CD8+ Lymphocytes Control Viral Replication in SIVmac239-Infected Rhesus Macaques without Decreasing the Lifespan of Productively Infected Cells. PLoS Pathog 6(1): e32767. doi:10.1371/journal.ppat.1000747
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000747

Souhrn

While CD8+ T cells are clearly important in controlling virus replication during HIV and SIV infections, the mechanisms underlying this antiviral effect remain poorly understood. In this study, we assessed the in vivo effect of CD8+ lymphocyte depletion on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques. We treated two groups of animals that were either CD8+ lymphocyte-depleted or controls with antiretroviral therapy, and used mathematical modeling to assess the lifespan of infected cells either in the presence or absence of CD8+ lymphocytes. We found that, in both early (day 57 post-SIV) and late (day 177 post-SIV) chronic SIV infection, depletion of CD8+ lymphocytes did not result in a measurable increase in the lifespan of either short- or long-lived productively infected cells in vivo. This result indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication.


Zdroje

1. GarberDA

SilvestriG

FeinbergMB

2004 Prospects for an AIDS vaccine: three big questions, no easy answers. Lancet Infect Dis 4 397 413

2. Coordinating Committee of the Global HIV/AIDS Vaccine Enterprise 2005 The Global HIV/AIDS Vaccine Enterprise: scientific strategic plan. PLoS Med 2 e25 doi:10.1371/journal.pmed.0020025

3. WalkerBD

BurtonDR

2008 Toward an AIDS vaccine. Science 320 760 764

4. WatkinsDI

BurtonDR

KallasEG

MooreJP

KoffWC

2008 Nonhuman primate models and the failure of the Merck HIV-1 vaccine in humans. Nat Med 14 617 621

5. PantophletR

BurtonDR

2006 GP120: target for neutralizing HIV-1 antibodies. Annu Rev Immunol 24 739 769

6. HuSL

StamatatosL

2007 Prospects of HIV Env modification as an approach to HIV vaccine design. Curr HIV Res 5 507 513

7. Karlsson HedestamGB

FouchierRA

PhogatS

BurtonDR

SodroskiJ

2008 The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nat Rev Microbiol 6 143 155

8. LetvinNL

2007 Correlates of immune protection and the development of a human immunodeficiency virus vaccine. Immunity 27 366 369

9. MillerJD

MasopustD

WherryEJ

KaechS

SilvestriG

2005 Differentiation of CD8 T cells in response to acute and chronic viral infections: implications for HIV vaccine development. Curr Drug Targets Infect Disord 5 121 129

10. HarariA

DutoitV

CelleraiC

BartPA

Du PasquierRA

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

11. WalkerCM

MoodyDJ

StitesDP

LevyJA

1986 CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 234 1563 1566

12. KannagiM

ChalifouxLV

LordCI

LetvinNL

1988 Suppression of simian immunodeficiency virus replication in vitro by CD8+ lymphocytes. J Immunol 140 2237 2242

13. BrummeZL

HarriganPR

2006 The impact of human genetic variation on HIV disease in the era of HAART. AIDS Rev 8 78 87

14. GoulderPJ

WatkinsDI

2004 HIV and SIV CTL escape: implications for vaccine design. Nat Rev Immunol 4 630 640

15. KoupRA

SafritJT

CaoY

AndrewsCA

McLeodG

1994 Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 68 4650 4655

16. BorrowP

LewickiH

HahnBH

ShawGM

OldstoneMB

1994 Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 68 6103 6110

17. SchmitzJE

KurodaMJ

SantraS

SassevilleVG

SimonMA

1999 Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283 857 860

18. JinX

BauerDE

TuttletonSE

LewinS

GettieA

1999 Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 189 991 998

19. MatanoT

ShibataR

SiemonC

ConnorsM

LaneHC

1998 Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol 72 164 169

20. LifsonJD

RossioJL

PiatakMJr

ParksT

LiL

2001 Role of CD8(+) lymphocytes in control of simian immunodeficiency virus infection and resistance to rechallenge after transient early antiretroviral treatment. J Virol 75 10187 10199

21. Van RompayKK

SinghRP

PaharB

SodoraDL

WingfieldC

2004 CD8+-cell-mediated suppression of virulent simian immunodeficiency virus during tenofovir treatment. J Virol 78 5324 5337

22. PerelsonAS

EssungerP

CaoY

VesanenM

HurleyA

1997 Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387 188 191

23. HoDD

NeumannAU

PerelsonAS

ChenW

LeonardJM

1995 Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373 123 126

24. WeiX

GhoshSK

TaylorME

JohnsonVA

EminiEA

1995 Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373 117 122

25. NowakMA

LloydAL

VasquezGM

WiltroutTA

WahlLM

1997 Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection. J Virol 71 7518 7525

26. GordonSN

DunhamRM

EngramJC

EstesJ

WangZ

2008 Short-lived infected cells support virus replication in sooty mangabeys naturally infected with simian immunodeficiency virus: implications for AIDS pathogenesis. J Virol 82 3725 3735

27. PandreaI

RibeiroRM

GautamR

GaufinT

PattisonM

2008 Simian immunodeficiency virus SIVagm dynamics in African green monkeys. J Virol 82 3713 3724

28. MittlerJE

MarkowitzM

HoDD

PerelsonAS

1999 Improved estimates for HIV-1 clearance rate and intracellular delay. AIDS 13 1415 1417

29. NotermansDW

GoudsmitJ

DannerSA

de WolfF

PerelsonAS

1998 Rate of HIV-1 decline following antiretroviral therapy is related to viral load at baseline and drug regimen. AIDS 12 1483 1490

30. PerelsonAS

NeumannAU

MarkowitzM

LeonardJM

HoDD

1996 HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271 1582 1586

31. BarryAP

SilvestriG

SafritJT

SumpterB

KozyrN

2007 Depletion of CD8+ Cells in Sooty Mangabey Monkeys Naturally Infected with Simian Immunodeficiency Virus Reveals Limited Role for Immune Control of Virus Replication in a Natural Host Species. J Immunol 178 8002 8012

32. KlattNR

VillingerF

BostikP

GordonSN

PereiraL

2008 Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys. J Clin Invest 118 2039 2049

33. 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

34. D'SouzaM

FontenotAP

MackDG

LozuponeC

DillonS

2007 Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction. J Immunol 179 1979 1987

35. PetrovasC

CasazzaJP

BrenchleyJM

PriceDA

GostickE

2006 PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 203 2281 2292

36. TrautmannL

JanbazianL

ChomontN

SaidEA

GimmigS

2006 Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12 1198 1202

37. JonesRB

NdhlovuLC

BarbourJD

ShethPM

JhaAR

2008 Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med 205 2763 2779

38. VeluV

KannanganatS

IbegbuC

ChennareddiL

VillingerF

2007 Elevated expression levels of inhibitory receptor programmed death 1 on simian immunodeficiency virus-specific CD8 T cells during chronic infection but not after vaccination. J Virol 81 5819 5828

39. PetrovasC

PriceDA

MattapallilJ

AmbrozakDR

GeldmacherC

2007 SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection. Blood 110 928 936

40. TsubotaH

LordCI

WatkinsDI

MorimotoC

LetvinNL

1989 A cytotoxic T lymphocyte inhibits acquired immunodeficiency syndrome virus replication in peripheral blood lymphocytes. J Exp Med 169 1421 1434

41. 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

42. WalkerCM

LevyJA

1989 A diffusible lymphokine produced by CD8+ T lymphocytes suppresses HIV replication. Immunology 66 628 630

43. LevyJA

2003 The search for the CD8+ cell anti-HIV factor (CAF). Trends Immunol 24 628 632

44. CocchiF

DeVicoAL

Garzino-DemoA

AryaSK

GalloRC

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

45. MooreJP

TrkolaA

DragicT

1997 Co-receptors for HIV-1 entry. Curr Opin Immunol 9 551 562

46. AlterG

AltfeldM

2009 NK cells in HIV-1 infection: evidence for their role in the control of HIV-1 infection. J Intern Med 265 29 42

47. AlterG

AltfeldM

2006 NK cell function in HIV-1 infection. Curr Mol Med 6 621 629

48. AlterG

MalenfantJM

DelabreRM

BurgettNC

YuXG

2004 Increased natural killer cell activity in viremic HIV-1 infection. J Immunol 173 5305 5311

49. FauciAS

MavilioD

KottililS

2005 NK cells in HIV infection: paradigm for protection or targets for ambush. Nat Rev Immunol 5 835 843

50. KosubDA

LehrmanG

MilushJM

ZhouD

ChackoE

2008 Gamma/Delta T-cell functional responses differ after pathogenic human immunodeficiency virus and nonpathogenic simian immunodeficiency virus infections. J Virol 82 1155 1165

51. KlenermanP

PhillipsRE

RinaldoCR

WahlLM

OggG

1996 Cytotoxic T lymphocytes and viral turnover in HIV type 1 infection. Proc Natl Acad Sci U S A 93 15323 15328

52. SachaJB

ChungC

RakaszEG

SpencerSP

JonasAK

2007 Gag-specific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and viral protein expression. J Immunol 178 2746 2754

53. DolanMJ

KulkarniH

CamargoJF

HeW

SmithA

2007 CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms. Nat Immunol 8 1324 1336

54. GarberDA

SilvestriG

BarryAP

FedanovA

KozyrN

2004 Blockade of T cell costimulation reveals interrelated actions of CD4+ and CD8+ T cells in control of SIV replication. J Clin Invest 113 836 845

55. DunhamR

PagliardiniP

GordonS

SumpterB

EngramJ

2006 The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus. Blood 108 209 217

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2010 Číslo 1
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#