#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

In Vivo CD8+ T-Cell Suppression of SIV Viremia Is Not Mediated by CTL Clearance of Productively Infected Cells


The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV) infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV. As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication. Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL) killing. Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle. These observations have important implications for future strategies to augment immune control of HIV.


Vyšlo v časopise: In Vivo CD8+ T-Cell Suppression of SIV Viremia Is Not Mediated by CTL Clearance of Productively Infected Cells. PLoS Pathog 6(1): e32767. doi:10.1371/journal.ppat.1000748
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000748

Souhrn

The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV) infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV. As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication. Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL) killing. Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle. These observations have important implications for future strategies to augment immune control of HIV.


Zdroje

1. BorrowP

LewickiH

WeiX

HorwitzMS

PefferN

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

2. 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

3. MooreJP

CaoY

HoDD

KoupRA

1994 Development of the anti-gp120 antibody response during seroconversion to human immunodeficiency virus type 1. J Virol 68 5142 5155

4. 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

5. OggGS

JinX

BonhoefferS

DunbarPR

NowakMA

1998 Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279 2103 2106

6. SchmitzJE

KurodaMJ

SantraS

SassevilleVG

SimonMA

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

7. 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

8. 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

9. SchmitzJE

KurodaMJ

SantraS

SimonMA

LiftonMA

2003 Effect of humoral immune responses on controlling viremia during primary infection of rhesus monkeys with simian immunodeficiency virus. J Virol 77 2165 2173

10. JohnstonMI

FauciAS

2007 An HIV vaccine–evolving concepts. N Engl J Med 356 2073 2081

11. SekalyRP

2008 The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development? J Exp Med 205 7 12

12. CastroBA

HomsyJ

LennetteE

MurthyKK

EichbergJW

1992 HIV-1 expression in chimpanzees can be activated by CD8+ cell depletion or CMV infection. Clin Immunol Immunopathol 65 227 233

13. WeiX

GhoshSK

TaylorME

JonsonVA

EminiEA

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

14. 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

15. HoDD

NeumannAU

PerelsonAS

ChenW

LeonardJM

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

16. LouieM

HoganC

Di MascioM

HurleyA

SimonV

2003 Determining the relative efficacy of highly active antiretroviral therapy. J Infect Dis 187 896 900

17. LeuteneggerCM

HigginsJ

MatthewsTB

TarantalAF

LuciwPA

2001 Real-time TaqMan PCR as a specific and more sensitive alternative to the branched-chain DNA assay for quantitation of simian immunodeficiency virus RNA. AIDS Res Hum Retroviruses 17 243 251

18. GeorgeMD

ReayE

SankaranS

DandekarS

2005 Early antiretroviral therapy for simian immunodeficiency virus infection leads to mucosal CD4+ T-cell restoration and enhanced gene expression regulating mucosal repair and regeneration. J Virol 79 2709 2719

19. VerhoevenD

SankaranS

SilveyM

DandekarS

2008 Antiviral therapy during primary simian immunodeficiency virus infection fails to prevent acute loss of CD4+ T cells in gut mucosa but enhances their rapid restoration through central memory T cells. J Virol 82 4016 4027

20. FelsensteinJ

1993 Phylogenetic Inference Package (Phylip) 3.5 University of Washington

21. NeiM

GojoboriT

1986 Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 3 418 426

22. NowakMA

LloydAL

VasquezGM

WiltroutTA

WahlLM

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

23. SchmitzJE

JohnsonRP

McClureHM

MansonKH

WyandMS

2005 Effect of CD8+ lymphocyte depletion on virus containment after simian immunodeficiency virus SIVmac251 challenge of live attenuated SIVmac239delta3-vaccinated rhesus macaques. J Virol 79 8131 8141

24. KimEY

VeazeyRS

ZahnR

McEversKJ

BaumeisterSH

2008 Contribution of CD8+ T cells to containment of viral replication and emergence of mutations in Mamu-A*01-restricted epitopes in Simian immunodeficiency virus-infected rhesus monkeys. J Virol 82 5631 5635

25. JohnstonMI

FauciAS

2008 An HIV vaccine–challenges and prospects. N Engl J Med 359 888 890

26. WalkerCM

LevyJA

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

27. WalkerCM

MoodyDJ

StitesDP

LevyJA

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

28. CocchiF

DeVicoAL

Garzino-DemoA

AryaSK

GalloRC

1995 Identification of Rantes, MIP-1a, and MIP-1b as the major HIV-suppressive factors produced by CD8+ T-Cells. Science 270 1811 1815

29. 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

30. KlattNR

ShudoE

OrtizAM

EngramJC

PaiardiniM

2010 CD8+ lymphocytes control viral replication in SIVmac239-infected rhesus macaques without decreasing the lifespan of productively infected cells. PLoS Pathog 6 e1000747 doi:10.1371/journal.ppat.1000747

31. OkoyeA

ParkH

RohankhedkarM

Coyne-JohnsonL

LumR

2009 Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis. J Exp Med 206 1575 1588

32. 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

33. KilbyJM

LeeHY

HazelwoodJD

BansalA

BucyRP

2008 Treatment response in acute/early infection versus advanced AIDS: equivalent first and second phases of HIV RNA decline. Aids 22 957 962

34. OxeniusA

McLeanAR

FischerM

PriceDA

DawsonSJ

2002 Human immunodeficiency virus-specific CD8(+) T-cell responses do not predict viral growth and clearance rates during structured intermittent antiretroviral therapy. J Virol 76 10169 10176

35. 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

36. 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

37. 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

38. KlotmanME

KimS

BuchbinderA

DeRossiA

BaltimoreD

1991 Kinetics of expression of multiply spliced RNA in early human immunodeficiency virus type 1 infection of lymphocytes and monocytes. Proc Natl Acad Sci USA 88 5011 5015

39. KimS-Y

ByrnR

GroopmanJ

BaltimoreD

1989 Temporal aspects of DNA and RNA synthesis during human immunodeficiency virus infection: evidence for differential gene expression. Journal of Virology 63 3708 3713

40. CollinsKL

BaltimoreD

1999 HIV's evasion of the cellular immune response. Immunol Rev 168 65 74

41. CollinsKL

ChenBK

KalamsSA

WalkerBD

BaltimoreD

1998 HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391 397 401

42. KaiserP

JoosB

NiederostB

WeberR

GunthardHF

2007 Productive human immunodeficiency virus type 1 infection in peripheral blood predominantly takes place in CD4/CD8 double-negative T lymphocytes. J Virol 81 9693 9706

43. HuberM

FischerM

MisselwitzB

ManriqueA

KusterH

2006 Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 infection. PLoS Med 3 e441

44. AlterG

AltfeldM

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

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

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

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#