Functional Cure of SIVagm Infection in Rhesus Macaques Results in Complete Recovery of CD4 T Cells and Is Reverted by CD8 Cell Depletion

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Understanding the mechanism of infection control in elite controllers (EC) may shed light on the correlates of control of disease progression in HIV infection. However, limitations have prevented a clear understanding of the mechanisms of elite controlled infection, as these studies can only be performed at randomly selected late time points in infection, after control is achieved, and the access to tissues is limited. We report that SIVagm infection is elite-controlled in rhesus macaques (RMs) and therefore can be used as an animal model for EC HIV infection. A robust acute infection, with high levels of viral replication and dramatic mucosal CD4⁺ T cell depletion, similar to pathogenic HIV-1/SIV infections of humans and RMs, was followed by complete and durable control of SIVagm replication, defined as: undetectable VLs in blood and tissues beginning 72 to 90 days postinoculation (pi) and continuing at least 4 years; seroreversion; progressive recovery of mucosal CD4⁺ T cells, with complete recovery by 4 years pi; normal levels of T cell immune activation, proliferation, and apoptosis; and no disease progression. This “functional cure” of SIVagm infection in RMs could be reverted after 4 years of control of infection by depleting CD8 cells, which resulted in transient rebounds of VLs, thus suggesting that control may be at least in part immune mediated. Viral control was independent of MHC, partial APOBEC restriction was not involved in SIVagm control in RMs and Trim5 genotypes did not impact viral replication. This new animal model of EC lentiviral infection, in which complete control can be predicted in all cases, permits research on the early events of infection in blood and tissues, before the defining characteristics of EC are evident and when host factors are actively driving the infection towards the EC status.

Vyšlo v časopise: Functional Cure of SIVagm Infection in Rhesus Macaques Results in Complete Recovery of CD4 T Cells and Is Reverted by CD8 Cell Depletion. PLoS Pathog 7(8): e32767. doi:10.1371/journal.ppat.1002170
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002170

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

2. BakerBMBlockBLRothchildACWalkerBD 2009 Elite control of HIV infection: implications for vaccine design. Expert Opin Biol Ther 9 55 69

3. HirschVMJohnsonPR 1994 Pathogenic diversity of simian immunodeficiency viruses. Virus Res 32 183 203

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

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

6. MellorsJWRinaldoCRJrGuptaPWhiteRMToddJA 1996 Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272 1167 1170

7. GrossmanZMeier-SchellersheimMPaulWEPickerLJ 2006 Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med 12 289 295

8. BrenchleyJMSchackerTWRuffLEPriceDATaylorJH 2004 CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 200 749 759

9. MehandruSPolesMATenner-RaczKHorowitzAHurleyA 2004 Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med 200 761 770

10. VeazeyRSDeMariaMChalifouxLVShvetzDEPauleyDR 1998 Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280 427 431

11. GiorgiJVHultinLEMcKeatingJAJohnsonTDOwensB 1999 Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis 179 859 870

12. KoupRASafritJTCaoYAndrewsCAMcLeodG 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

13. SilicianoR 2000 Can antiretroviral therapy ever be stopped? AIDS Read 10 224 229

14. RichmanDD 2001 HIV chemotherapy. Nature 410 995 1001

15. DesrosiersRC 2004 Prospects for an AIDS vaccine. Nat Med 10 221 223

16. 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

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

18. AddoMMDraenertRRathodAVerrillCLDavisBT 2007 Fully differentiated HIV-1 specific CD8+ T effector cells are more frequently detectable in controlled than in progressive HIV-1 infection. PLoS ONE 2 e321

19. LoffredoJTMaxwellJQiYGliddenCEBorchardtGJ 2007 Mamu-B*08-positive Macaques Control Simian Immunodeficiency Virus Replication. J Virol 81 8827 8832

20. YantLJFriedrichTCJohnsonRCMayGEManessNJ 2006 The high-frequency major histocompatibility complex class I allele Mamu-B*17 is associated with control of simian immunodeficiency virus SIVmac239 replication. J Virol 80 5074 5077

21. PandreaIApetreiCDufourJDillonNBarbercheckJ 2006 Simian immunodeficiency virus (SIV) SIVagm.sab infection of Caribbean African green monkeys: New model of the study of SIV pathogenesis in natural hosts. J Virol 80 4858 4867

22. PandreaISilvestriGOnangaRVeazeyRSMarxPA 2006 Simian immunodeficiency viruses replication dynamics in African non-human primate hosts: common patterns and species-specific differences. J Med Primatol 35 194 201

23. PandreaIOnangaRKornfeldCRouquetPBourryO 2003 High levels of SIVmnd-1 replication in chronically infected Mandrillus sphinx. Virology 317 119 127

24. GaufinTPattisonMGautamRStouligCDufourJ 2009 Effect of B cell depletion on viral replication and clinical outcome of SIV infection in a natural host. J Virol 83 10347 10357

25. PickerLJHagenSILumRReed-InderbitzinEFDalyLM 2004 Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J Exp Med 200 1299 1314

26. PawarSNMattilaJTSturgeonTJLinPLNarayanO 2008 Comparison of the effects of pathogenic simian human immunodeficiency virus strains SHIV-89.6P and SHIV-KU2 in cynomolgus macaques. AIDS Res Hum Retroviruses 24 643 654

27. HansenSGFordJCLewisMSVenturaABHughesCM Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473 523 527

28. LingBMohanMLacknerAAGreenLCMarxPA 2010 The large intestine as a major reservoir for simian immunodeficiency virus in macaques with long-term, nonprogressing infection. J Infect Dis 202 1846 1854

29. PandreaIKornfeldCPloquinMJ-IApetreiCFayeA 2005 Impact of viral factors on very early in vivo replication profiles in SIVagm-infected African green monkeys. J Virol 79 6249 6259

30. GnanaduraiCWPandreaIParrishNFKrausMHLearnGH 2010 Genetic identity and biological phenotype of a Transmitted/Founder virus representative of non-pathogenic simian immunodeficiency virus infection in African green monkeys. J Virol 84 12245 12254

31. PandreaIGautamRRibeiroRBrenchleyJMButlerIF 2007 Acute loss of intestinal CD4+ T cells is not predictive of SIV virulence. J Immunol 179 3035 3046

32. VandeWoudeSApetreiC 2006 Going wild: Lessons from T-lymphotropic naturally occurring lentiviruses. Clin Microbiol Rev 19 728 762

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

34. LiQDuanLEstesJDMaZMRourkeT 2005 Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434 1148 1152

35. BrenchleyJMPriceDASchackerTWAsherTESilvestriG 2006 Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Medicine 12 1365 1371

36. PossMRossHAPainterSLHolleyDCTerweeJA 2006 Feline lentivirus evolution in cross-species infection reveals extensive G-to-A mutation and selection on key residues in the viral polymerase. J Virol 80 2728 2737

37. KirmaierAWuFNewmanRMHallLRMorganJS TRIM5 suppresses cross-species transmission of a primate immunodeficiency virus and selects for emergence of resistant variants in the new species. PLoS Biol 8 e1000462

38. MullerMCBarre-SinoussiF 2003 SIVagm: genetic and biological features associated with replication. Front Biosci 8 D1170 1185

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

40. GautamRGaufinTButlerIGautamABarnesM 2009 SIVrcm, a unique CCR2-tropic virus, selectively depletes memory CD4+ T cells in pigtailed macaques through rapid coreceptor expansion in vivo. J Virol 83 7894 7908

41. ApetreiCGaufinTGautamRVintonCHirschVM 2010 Pattern of SIVagm infection in patas monkeys suggests that host adaptation to SIV infection may result in resistance to infection and virus extinction. J Infect Dis 202 Suppl 3 S371 376

42. HatanoHDelwartELNorrisPJLeeTHNeilandsTB Evidence of persistent low-level viremia in long-term HAART-suppressed, HIV-infected individuals. AIDS 24 2535 2539

43. PalmerSMaldarelliFWiegandABernsteinBHannaGJ 2008 Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A 105 3879 3884

44. KelleyCFKitchenCMHuntPWRodriguezBHechtFM 2009 Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis 48 787 794

45. AllersKHutterGHofmannJLoddenkemperCRiegerK Evidence for the cure of HIV infection by CCR5 Delta32/Delta32 stem cell transplantation. Blood 117 2791 2799

46. DesrosiersRCLifsonJDGibbsJSCzajakSCHoweAY 1998 Identification of highly attenuated mutants of simian immunodeficiency virus. J Virol 72 1431 1437

47. BlanksonJNBaileyJRThayilSYangHCLassenK 2007 Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors. J Virol 81 2508 2518

48. CarruthLMZinkMCTarwaterPMMillerMDLiM 2005 SIV-specific T lymphocyte responses in PBMC and lymphoid tissues of SIV-infected pigtailed macaques during suppressive combination antiretroviral therapy. J Med Primatol 34 109 121

49. LingBVeazeyRSHartMLacknerAAKurodaM 2007 Early restoration of mucosal CD4 memory CCR5 T cells in the gut of SIV-infected rhesus predicts long term non-progression. Aids 21 2377 2385

50. GautamRCarterACKatzNButlerIFBarnesM 2007 In vitro characterization of primary SIVsmm isolates belonging to different lineages. In vitro growth on rhesus macaque cells is not predictive for in vivo replication in rhesus macaques. Virology 362 257 270

51. HuntPW 2009 Natural control of HIV-1 replication and long-term nonprogression: overlapping but distinct phenotypes. J Infect Dis 200 1636 1638

52. HuntPWBrenchleyJSinclairEMcCuneJMRolandM 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

53. RichmanDDMargolisDMDelaneyMGreeneWCHazudaD 2009 The challenge of finding a cure for HIV infection. Science 323 1304 1307

54. HsuePYHuntPWSchnellAKalapusSCHohR 2009 Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS 23 1059 1067

55. GaufinTGautamRKashetaMRibeiroRMRibkaE 2009 Limited ability of humoral immune responses in control of viremia during infection with SIVsmmD215 strain. Blood 113 4250 4261

56. SimonFSouquiereSDamondFKfutwahAMakuwaM 2001 Synthetic peptide strategy for the detection of and discrimination among highly divergent primate lentiviruses. AIDS Res Hum Retroviruses 17 937 952

57. DigglePJHeagertyPLaingK-YZegerSL 2002 Analysis of longitudinal data. Oxford, UK Oxford University Press