Targeted Cytotoxic Therapy Kills Persisting HIV Infected Cells During ART

English version České info

Antiretroviral therapy (ART) can reduce HIV levels in plasma to undetectable levels, but rather little is known about the effects of ART outside of the peripheral blood regarding persistent virus production in tissue reservoirs. Understanding the dynamics of ART-induced reductions in viral RNA (vRNA) levels throughout the body is important for the development of strategies to eradicate infectious HIV from patients. Essential to a successful eradication therapy is a component capable of killing persisting HIV infected cells during ART. Therefore, we determined the in vivo efficacy of a targeted cytotoxic therapy to kill infected cells that persist despite long-term ART. For this purpose, we first characterized the impact of ART on HIV RNA levels in multiple organs of bone marrow-liver-thymus (BLT) humanized mice and found that antiretroviral drug penetration and activity was sufficient to reduce, but not eliminate, HIV production in each tissue tested. For targeted cytotoxic killing of these persistent vRNA⁺ cells, we treated BLT mice undergoing ART with an HIV-specific immunotoxin. We found that compared to ART alone, this agent profoundly depleted productively infected cells systemically. These results offer proof-of-concept that targeted cytotoxic therapies can be effective components of HIV eradication strategies.

Vyšlo v časopise: Targeted Cytotoxic Therapy Kills Persisting HIV Infected Cells During ART. PLoS Pathog 10(1): e32767. doi:10.1371/journal.ppat.1003872
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003872

Souhrn

Zdroje

1. NakagawaF, MayM, PhillipsA (2013) Life expectancy living with HIV: recent estimates and future implications. Curr Opin Infect Dis 26: 17–25.

2. RichmanDD, MargolisDM, DelaneyM, GreeneWC, HazudaD, et al. (2009) The challenge of finding a cure for HIV infection. Science 323: 1304–1307.

3. DeeksSG, AutranB, BerkhoutB, BenkiraneM, CairnsS, et al. (2012) Towards an HIV cure: a global scientific strategy. Nat Rev Immunol 12: 607–614.

4. DurandCM, BlanksonJN, SilicianoRF (2012) Developing strategies for HIV-1 eradication. Trends Immunol 33: 554–562.

5. DeeksSG (2012) HIV: Shock and kill. Nature 487: 439–440.

6. ShanL, DengK, ShroffNS, DurandCM, RabiSA, et al. (2012) Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 36: 491–501.

7. HamerDH (2004) Can HIV be Cured? Mechanisms of HIV persistence and strategies to combat it. Curr HIV Res 2: 99–111.

8. BergerEA, PastanI (2010) Immunotoxin complementation of HAART to deplete persisting HIV-infected cell reservoirs. PLoS Pathog 6: e1000803.

9. ThrushGR, LarkLR, ClinchyBC, VitettaES (1996) Immunotoxins: an update. Annu Rev Immunol 14: 49–71.

10. PincusSH (1996) Therapeutic potential of anti-HIV immunotoxins. Antiviral Res 33: 1–9.

11. Van OijenMG, PreijersFW (1998) Rationale for the use of immunotoxins in the treatment of HIV-infected humans. J Drug Target 5: 75–91.

12. LiuS, SchubertRL, BuggeTH, LepplaSH (2003) Anthrax toxin: structures, functions and tumour targeting. Expert Opin Biol Ther 3: 843–853.

13. EngertA, SausvilleEA, VitettaE (1998) The emerging role of ricin A-chain immunotoxins in leukemia and lymphoma. Curr Top Microbiol Immunol 234: 13–33.

14. TillMA, Zolla-PaznerS, GornyMK, PattonJS, UhrJW, et al. (1989) Human immunodeficiency virus-infected T cells and monocytes are killed by monoclonal human anti-gp41 antibodies coupled to ricin A chain. Proc Natl Acad Sci U S A 86: 1987–1991.

15. PincusSH, WehrlyK, ChesebroB (1989) Treatment of HIV tissue culture infection with monoclonal antibody-ricin A chain conjugates. J Immunol 142: 3070–3075.

16. TillMA, GhetieV, GregoryT, PatzerEJ, PorterJP, et al. (1988) HIV-infected cells are killed by rCD4-ricin A chain. Science 242: 1166–1168.

17. ChaudharyVK, MizukamiT, FuerstTR, FitzGeraldDJ, MossB, et al. (1988) Selective killing of HIV-infected cells by recombinant human CD4-Pseudomonas exotoxin hybrid protein. Nature 335: 369–372.

18. BergerEA, ClouseKA, ChaudharyVK, ChakrabartiS, FitzGeraldDJ, et al. (1989) CD4-Pseudomonas exotoxin hybrid protein blocks the spread of human immunodeficiency virus infection in vitro and is active against cells expressing the envelope glycoproteins from diverse primate immunodeficiency retroviruses. Proc Natl Acad Sci U S A 86: 9539–9543.

19. BellKD, RamiloO, VitettaES (1993) Combined use of an immunotoxin and cyclosporine to prevent both activated and quiescent peripheral blood T cells from producing type 1 human immunodeficiency virus. Proc Natl Acad Sci U S A 90: 1411–1415.

20. McCoigC, Van DykeG, ChouCS, PickerLJ, RamiloO, et al. (1999) An anti-CD45RO immunotoxin eliminates T cells latently infected with HIV-1 in vitro. Proc Natl Acad Sci U S A 96: 11482–11485.

21. PincusSH, McClureJ (1993) Soluble CD4 enhances the efficacy of immunotoxins directed against gp41 of the human immunodeficiency virus. Proc Natl Acad Sci U S A 90: 332–336.

22. BeraTK, KennedyPE, BergerEA, BarbasCF3rd, PastanI (1998) Specific killing of HIV-infected lymphocytes by a recombinant immunotoxin directed against the HIV-1 envelope glycoprotein. Mol Med 4: 384–391.

23. CoryTJ, SchackerTW, StevensonM, FletcherCV (2013) Overcoming pharmacologic sanctuaries. Curr Opin HIV AIDS 8: 190–195.

24. MelkusMW, EstesJD, Padgett-ThomasA, GatlinJ, DentonPW, et al. (2006) Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med 12: 1316–1322.

25. DentonPW, GarciaJV (2011) Humanized mouse models of HIV infection. AIDS Rev 13: 135–148.

26. DentonPW, GarciaJV (2012) Mucosal HIV-1 transmission and prevention strategies in BLT humanized mice. Trends Microbiol 20: 268–274.

27. DentonPW, NochiT, LimA, KriskoJF, Martinez-TorresF, et al. (2012) IL-2 receptor gamma-chain molecule is critical for intestinal T-cell reconstitution in humanized mice. Mucosal Immunol 5: 555–566.

28. LongBR, StoddartCA (2012) Alpha interferon and HIV infection cause activation of human T cells in NSG-BLT mice. J Virol 86: 3327–3336.

29. BrainardDM, SeungE, FrahmN, CariappaA, BaileyCC, et al. (2009) Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice. J Virol 83: 7305–7321.

30. ZouW, DentonPW, WatkinsRL, KriskoJF, NochiT, et al. (2012) Nef functions in BLT mice to enhance HIV-1 replication and deplete CD4+CD8+ thymocytes. Retrovirology 9: 44.

31. SunZ, DentonPW, EstesJD, OthienoFA, WeiBL, et al. (2007) Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1. J Exp Med 204: 705–714.

32. DentonPW, EstesJD, SunZ, OthienoFA, WeiBL, et al. (2008) Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med 5: e16.

33. JilekBL, ZarrM, SampahME, RabiSA, BullenCK, et al. (2012) A quantitative basis for antiretroviral therapy for HIV-1 infection. Nat Med 18: 446–451.

34. RockstrohJK, DejesusE, LennoxJL, YazdanpanahY, SaagMS, et al. (2013) Durable Efficacy and Safety of Raltegravir versus Efavirenz When Combined With Tenofovir/Emtricitabine In Treatment-Naive HIV-1 Infected Patients: Final Five-Year Results From STARTMRK. J Acquir Immune Defic Syndr 63 (1) 77–85.

35. DentonPW, OlesenR, ChoudharySK, ArchinNM, WahlA, et al. (2012) Generation of HIV latency in BLT humanized mice. J Virol 86: 630–634.

36. PalmerS, MaldarelliF, WiegandA, BernsteinB, HannaGJ, et al. (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.

37. AutranB, CarcelainG, LiTS, BlancC, MathezD, et al. (1997) Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277: 112–116.

38. MurrayJM, McBrideK, BoeseckeC, BaileyM, AminJ, et al. (2012) Integrated HIV DNA accumulates prior to treatment while episomal HIV DNA records ongoing transmission afterwards. AIDS 26: 543–550.

39. RobbinsBL, SrinivasRV, KimC, BischofbergerN, FridlandA (1998) Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob Agents Chemother 42: 612–617.

40. SchinaziRF, McMillanA, CannonD, MathisR, LloydRM, et al. (1992) Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother 36: 2423–2431.

41. ScopellitiF, PollicitaM, Ceccherini-SilbersteinF, Di SantoF, SurdoM, et al. (2011) Comparative antiviral activity of integrase inhibitors in human monocyte-derived macrophages and lymphocytes. Antiviral Res 92: 255–261.

42. LafeuilladeA, KhiriH, ChadapaudS, HittingerG, HalfonP (2001) Persistence of HIV-1 resistance in lymph node mononuclear cell RNA despite effective HAART. AIDS 15: 1965–1969.

43. KennedyPE, BeraTK, WangQC, GalloM, WagnerW, et al. (2006) Anti-HIV-1 immunotoxin 3B3(Fv)-PE38: enhanced potency against clinical isolates in human PBMCs and macrophages, and negligible hepatotoxicity in macaques. J Leukoc Biol 80: 1175–1182.

44. GoldsteinH, Pettoello-MantovaniM, BeraTK, PastanIH, BergerEA (2000) Chimeric toxins targeted to the human immunodeficiency virus type 1 envelope glycoprotein augment the in vivo activity of combination antiretroviral therapy in thy/liv-SCID-Hu mice. J Infect Dis 181: 921–926.

45. BlanksonJN, FinziD, PiersonTC, SabundayoBP, ChadwickK, et al. (2000) Biphasic decay of latently infected CD4+ T cells in acute human immunodeficiency virus type 1 infection. J Infect Dis 182: 1636–1642.

46. SedaghatAR, DinosoJB, ShenL, WilkeCO, SilicianoRF (2008) Decay dynamics of HIV-1 depend on the inhibited stages of the viral life cycle. Proc Natl Acad Sci U S A 105: 4832–4837.

47. HorwitzJA, Halper-StrombergA, MouquetH, GitlinAD, TretiakovaA, et al. (2013) HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci U S A 110: 16538–16543.

48. BarbasCF3rd, HuD, DunlopN, SawyerL, CababaD, et al. (1994) In vitro evolution of a neutralizing human antibody to human immunodeficiency virus type 1 to enhance affinity and broaden strain cross-reactivity. Proc Natl Acad Sci U S A 91: 3809–3813.

49. NorthTW, HigginsJ, DeereJD, HayesTL, VillalobosA, et al. (2010) Viral sanctuaries during highly active antiretroviral therapy in a nonhuman primate model for AIDS. J Virol 84: 2913–2922.

50. YuklSA, ShergillAK, HoT, KillianM, GirlingV, et al. (2013) The distribution of HIV DNA and RNA in cell subsets differs in gut and blood of HIV-positive patients on ART: implications for viral persistence. J Infect Dis 208: 1212–1220.

51. WooJH, FrankelA, NevilleDM (2010) Cytotoxic therapy with diphtheria toxin fusion proteins. Drugs of the Future 35: 823–831.

52. WeldonJE, PastanI (2011) A guide to taming a toxin–recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancer. FEBS J 278: 4683–4700.

53. FangH, PincusSH (1995) Unique insertion sequence and pattern of CD4 expression in variants selected with immunotoxins from human immunodeficiency virus type 1-infected T cells. J Virol 69: 75–81.

54. BergerEA (2011) Targeted cytotoxic therapy: adapting a rapidly progressing anticancer paradigm for depletion of persistent HIV-infected cell reservoirs. Curr Opin HIV AIDS 6: 80–85.

55. MitsuyasuR (2013) Curing HIV: lessons from cancer therapy. Curr Opin HIV AIDS 8: 224–229.

56. DentonPW, OthienoF, Martinez-TorresF, ZouW, KriskoJF, et al. (2011) One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for evaluation of new microbicide candidates. J Virol 85: 7582–7593.

57. WahlA, SwansonMD, NochiT, OlesenR, DentonPW, et al. (2012) Human breast milk and antiretrovirals dramatically reduce oral HIV-1 transmission in BLT humanized mice. PLoS Pathog 8: e1002732.

58. KriskoJF, Martinez-TorresF, FosterJL, GarciaJV (2013) HIV Restriction by APOBEC3 in Humanized Mice. PLoS Pathog 9: e1003242.

59. HaaseAT, HenryK, ZupancicM, SedgewickG, FaustRA, et al. (1996) Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274: 985–989.