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 LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2010 Číslo 1
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Panton-Valentine Leukocidin Is a Very Potent Cytotoxic Factor for Human Neutrophils
- CD8+ T Cell Control of HIV—A Known Unknown
- Polyoma Virus-Induced Osteosarcomas in Inbred Strains of Mice: Host Determinants of Metastasis
- The Deadly Chytrid Fungus: A Story of an Emerging Pathogen