A Highly Intensified ART Regimen Induces Long-Term Viral Suppression and Restriction of the Viral Reservoir in a Simian AIDS Model
Stably suppressed viremia during ART is essential for establishing reliable simian models for HIV/AIDS. We tested the efficacy of a multidrug ART (highly intensified ART) in a wide range of viremic conditions (103–107 viral RNA copies/mL) in SIVmac251-infected rhesus macaques, and its impact on the viral reservoir. Eleven macaques in the pre-AIDS stage of the disease were treated with a multidrug combination (highly intensified ART) consisting of two nucleosidic/nucleotidic reverse transcriptase inhibitors (emtricitabine and tenofovir), an integrase inhibitor (raltegravir), a protease inhibitor (ritonavir-boosted darunavir) and the CCR5 blocker maraviroc. All animals stably displayed viral loads below the limit of detection of the assay (i.e. <40 RNA copies/mL) after starting highly intensified ART. By increasing the sensitivity of the assay to 3 RNA copies/mL, viral load was still below the limit of detection in all subjects tested. Importantly, viral DNA resulted below the assay detection limit (<2 copies of DNA/5*105 cells) in PBMCs and rectal biopsies of all animals at the end of the follow-up, and in lymph node biopsies from the majority of the study subjects. Moreover, highly intensified ART decreased central/transitional memory, effector memory and activated (HLA-DR+) effector memory CD4+ T-cells in vivo, in line with the role of these subsets as the main cell subpopulations harbouring the virus. Finally, treatment with highly intensified ART at viral load rebound following suspension of a previous anti-reservoir therapy eventually improved the spontaneous containment of viral load following suspension of the second therapeutic cycle, thus leading to a persistent suppression of viremia in the absence of ART. In conclusion, we show, for the first time, complete suppression of viral load by highly intensified ART and a likely associated restriction of the viral reservoir in the macaque AIDS model, making it a useful platform for testing potential cures for AIDS.
Vyšlo v časopise:
A Highly Intensified ART Regimen Induces Long-Term Viral Suppression and Restriction of the Viral Reservoir in a Simian AIDS Model. PLoS Pathog 8(6): e32767. doi:10.1371/journal.ppat.1002774
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002774
Souhrn
Stably suppressed viremia during ART is essential for establishing reliable simian models for HIV/AIDS. We tested the efficacy of a multidrug ART (highly intensified ART) in a wide range of viremic conditions (103–107 viral RNA copies/mL) in SIVmac251-infected rhesus macaques, and its impact on the viral reservoir. Eleven macaques in the pre-AIDS stage of the disease were treated with a multidrug combination (highly intensified ART) consisting of two nucleosidic/nucleotidic reverse transcriptase inhibitors (emtricitabine and tenofovir), an integrase inhibitor (raltegravir), a protease inhibitor (ritonavir-boosted darunavir) and the CCR5 blocker maraviroc. All animals stably displayed viral loads below the limit of detection of the assay (i.e. <40 RNA copies/mL) after starting highly intensified ART. By increasing the sensitivity of the assay to 3 RNA copies/mL, viral load was still below the limit of detection in all subjects tested. Importantly, viral DNA resulted below the assay detection limit (<2 copies of DNA/5*105 cells) in PBMCs and rectal biopsies of all animals at the end of the follow-up, and in lymph node biopsies from the majority of the study subjects. Moreover, highly intensified ART decreased central/transitional memory, effector memory and activated (HLA-DR+) effector memory CD4+ T-cells in vivo, in line with the role of these subsets as the main cell subpopulations harbouring the virus. Finally, treatment with highly intensified ART at viral load rebound following suspension of a previous anti-reservoir therapy eventually improved the spontaneous containment of viral load following suspension of the second therapeutic cycle, thus leading to a persistent suppression of viremia in the absence of ART. In conclusion, we show, for the first time, complete suppression of viral load by highly intensified ART and a likely associated restriction of the viral reservoir in the macaque AIDS model, making it a useful platform for testing potential cures for AIDS.
Zdroje
1. NorelliSEl DakerSD'OstilioDMeleFManciniF 2008 Response of feline immunodeficiency virus (FIV) to tipranavir may provide new clues for development of broad-based inhibitors of retroviral proteases acting on drug-resistant HIV-1 Curr. HIV Res 6 306 17
2. WitvrouwMPannecouqueCSwitzerWMFolksTMDe ClercqE 2004 Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds: implications for treatment and post exposure prophylaxis. Antivir Ther 9 57 65
3. DeereJDSchinaziRFNorthTW 2011 Simian immunodeficiency virus macaque models of HIV latency. Curr Opin HIV AIDS 6 57 61
4. DinosoJBRabiSABlanksonJNGamaLMankowskiJL 2009 A simian immunodeficiency virus-infected macaque model to study viral reservoirs that persist during highly active antiretroviral therapy. J Virol 83 9247 9257
5. LewisMGNorelliSCollinsMBarrecaMLIraciN 2010 Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treatment for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy. Retrovirology 7 21
6. VaheyMTOckenhouseCFWangZYalley-OgunroJGreenhouseJ 2007 Impact of antiretroviral treatment on gene expression in peripheral blood mononuclear cells from SIVmac251-infected macaques. J Infect Dis 196 384 393
7. LewisMGDafonsecaSChomontNPalamaraATTardugnoM 2011 Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension. AIDS 25 1347 56
8. ChomontNEl-FarMAncutaPTrautmannLProcopioFA 2009 HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 15 893 900
9. ChomontNDaFonsecaSVandergeetenCAncutaPSékalyRP 2011 Maintenance of CD4+ T-cell memory and HIV persistence: keeping memory, keeping HIV. Curr Opin HIV AIDS 6 30 6 Review
10. PaiardiniMCervasiBReyes-AvilesEMicciLOrtizAM 2011 Low levels of SIV infection in sooty mangabey central memory CD4+ T cells are associated with limited CCR5 expression. Nat Med 17 830 6
11. FultzPNStrickerRBMcClureHMAndersonDCSwitzerWM 1990 Humoral response to SIV/SMM infection in macaque and mangabey monkeys. J Acquir Immune Defic Syndr 3 319 29
12. LifsonJ 2012 The Role of Non-human Primate Models in the Evaluation of ARV Suppression, Residual Virus, and Viral Eradication Strategies in AIDS Virus Infection [Abstract 107]. In: Proceedings of the 19th Conference on Retroviruses and Opportunistic Infections; 5–8 March 2012, Seattle, Washington, United States. CROI 2012, Available: http://www.retroconference.org/2012b/Abstracts/45277.htm. Accessed 14 May 2012
13. BensiTMeleFFerrettiMNorelliSEl DakerS 2009 Evaluation of the antiretroviral effects of a PEG-conjugated peptide derived from human CD38. Expert Opin Ther Targets 13 141 52
14. KovalevskyAYLouisJMAnianaAGhoshAKWeberIT 2008 Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease. J Mol Biol 384 178 92
15. MuzammilSArmstrongAAKangLWJakalianABonneauPR 2007 Unique thermodynamic response of tipranavir to human immunodeficiency virus type 1 protease drug resistance mutations. J Virol 81 5144 54
16. ChenZZhouPHoDDLandauNRMarxPA 1997 Genetically divergent strains of simian immunodeficiency virus use CCR5 as a coreceptor for entry. J Virol 71 2705 14
17. VeazeyRSKlassePJKetasTJReevesJDPiatakMJr 2003 Use of a small molecule CCR5 inhibitor in macaques to treat simian immunodeficiency virus infection or prevent simian-human immunodeficiency virus infection. J Exp Med 198 1551 62
18. 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 84
19. SmithCJStaszewskiSSabinCANelsonMDauerB 2004 Use of viral load measured after 4 weeks of highly active antiretroviral therapy to predict virologic outcome at 24 weeks for HIV-1-positive individuals. J Acquir Immune Defic Syndr 37 1155 9
20. MiraJAMacíasJNogalesCFernández-RiveraJGarcía-GarcíaJA 2002 Transient rebounds of low-level viraemia among HIV-infected patients under HAART are not associated with virological or immunological failure. Antivir Ther 7 251 6
21. EllisRJGamstACCapparelliESpectorSAHsiaK 2000 Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology 54 927 36
22. KimRBFrommMFWandelCLeakeBWoodAJ 1998 The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 101 289 294
23. SavarinoALuciaMBRastrelliERutellaSGolottaC 2004 Anti-HIV effects of chloroquine: inhibition of viral particle glycosylation and synergism with proteaseinhibitors. J Acquir Immune Defic Syndr 35 223 32
24. BourryOManniouiASellierPRoucairolCDurand-GasselinL 2010 Effect of a short-term HAART on SIV load in macaque tissues is dependent on time of initiation and antiviral diffusion. Retrovirology 7 78
25. TurnerLWardSGSansomDWestwickJ 1996 A role for RANTES in T lymphocyte proliferation. Biochem Soc Trans 24 93S
26. GutiérrezCDíazLVallejoAHernández-NovoaBAbadM 2011 Intensification of antiretroviral therapy with a CCR5 antagonist in patients with chronic HIV-1 infection: effect on T cells latently infected. PLoS One 6 e27864
27. FunderburgNKalinowskaMEasonJGoodrichJHeeraJ 2010 Effects of maraviroc and efavirenz on markers of immune activation and inflammation and associations with CD4+ cell rises in HIV-infected patients. PLoS One 5 e13188
28. d'EttorreGPaiardiniMZaffiriLAndreottiMCeccarelliG 2011 HIV persistence in the gut mucosa of HIV-infected subjects undergoing antiretroviral therapy correlates with immune activation and increased levels of LPS. Curr HIV Res 9 148 53
29. HocquelouxLPrazuckTAvettand-FenoelVLafeuilladeACardonB 2010 Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. AIDS 24 1598 601
30. Benlhassan-ChahourKPenitCDioszeghyVVasseurFJanvierG 2003 Kinetics of lymphocyte proliferation during primary immune response in macaques infected with pathogenic simian immunodeficiency virus SIVmac251: preliminary report of the effect of early antiviral therapy. J Virol 77 12479 93
31. LoriFLewisMGXuJVargaGZinnDEJr 2000 Control of SIV rebound through structured treatment interruptions during early infection. Science 290 1591 3
32. LewinSRRouziouxC 2011 HIV cure and eradication: how will we get from the laboratory to effective clinical trials? AIDS 25 885 97
33. JohnstonRBarre-SinoussiF 2012 Controversies in HIV cure research. J Int AIDS Soc 15 16
34. MuddPAEricsenAJBurwitzBJWilsonNAO'ConnorDH 2012 Escape from CD8+ T Cell Responses in Mamu-B*00801+ Macaques Differentiates Progressors from Elite Controllers. J Immunol 188 3364 70
35. OrtizAMKlattNRLiBYiYTabbB 2011 Depletion of CD4+T cells abrogates post-peak decline of viremia in SIV-infected rhesus macaques. J Clin Invest 121 4433 45
36. GordonSNWeissmanARCecchinatoVFeniziaCMaZM 2010 Preexisting infection with human T-cell lymphotropic virus type 2 neither exacerbates nor attenuates simian immunodeficiency virus SIVmac251 infection in macaques. J Virol 84 3043 58
37. YehWWJaru-AmpornpanPNevidomskyteDAsmalMRaoSS 2009 Partial protection of Simian immunodeficiency virus (SIV)-infected rhesus monkeys against superinfection with a heterologous SIV isolate. J Virol 83 2686 96
38. ReimannKAParkerRASeamanMSBeaudryKBeddallM 2005 Pathogenicity of simian-human immunodeficiency virus SHIV-89.6P and SIVmac is attenuated in cynomolgus macaques and associated with early T-lymphocyte responses. J Virol 79 8878 85
39. SchackerTStevensonMFletcherC 2011 Anatomic HIV Reservoirs [Abstract 35]. In: Final Program and Abstracts of the 5th International Workshop on HIV Persistence during Therapy; St Maarten, West Indies, 6–9 December, 2011. Global Antiviral J 7 28 29
40. RongLPerelsonAS 2009 Modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in HIV-infected patients on potent therapy. PLoS Comput Biol 5 e1000533
41. ChenHYDi MascioMPerelsonASHoDDZhangL 2007 Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques. Proc Natl Acad Sci U S A 104 19079 84
42. AnanworanichJSchuetzAVandergeetenCSeretiIde SouzaM 2012 Impact of Multi-Targeted Antiretroviral Treatment on Gut T Cell Depletion and HIV Reservoir Seeding during Acute HIV Infection. PLoS One 7 e33948
43. GrootFvan CapelTMSchuitemakerJBerkhoutBde JongEC 2006 Differential susceptibility of naïve, central memory and effector memory T cells to dendritic cell-mediated HIV-1 transmission. Retrovirology 3 52
44. BostikPNobleESMayneAEGarganoLVillingerF 2006 Central memory CD4 T cells are the predominant cell subset resistant to anergy in SIV disease resistant sooty mangabeys. AIDS 20 181 8
45. ZhangZQFuTMCasimiroDRDaviesMELiangX 2002 Mamu-A*01 allele-mediated attenuation of disease progression in simian-human immunodeficiency virus infection. J Virol 76 12845 54
46. 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 7
47. LoffredoJTMaxwellJQiYGliddenCEBorchardtGJ 2007 Mamu-B*08-positive macaques control simian immunodeficiency virus replication. J Virol 81 16 8827 32
48. BoyerJDKumarSRobinsonTParkinsonRWuL 2006 Initiation of antiretroviral therapy during chronic SIV infection leads to rapid reduction in viral loads and the level of T-cell immune response. J Med Primatol 35 202 9
49. BacchettiPDeeksSGMcCuneJM 2011 Breaking free of sample size dogma to perform innovative translational research. Sci Transl Med 3 87
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2012 Číslo 6
- 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
- Manipulation of Costimulatory Molecules by Intracellular Pathogens: Veni, Vidi, Vici!!
- A Highly Intensified ART Regimen Induces Long-Term Viral Suppression and Restriction of the Viral Reservoir in a Simian AIDS Model
- An Endogenous Foamy-like Viral Element in the Coelacanth Genome
- Evidence for Induction of Integron-Based Antibiotic Resistance by the SOS Response in a Clinical Setting