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HIV Eradication Strategies: Implications for the Central Nervous System

  • Rebecca T. Veenhuis
  • Janice E. Clements
  • Lucio GamaEmail author
Central Nervous System and Cognition (SS Spudich, Section Editor)
  • 37 Downloads
Part of the following topical collections:
  1. Topical Collection on Central Nervous System and Cognition

Abstract

Purpose of Review

In addition to preventive protocols and antiretroviral therapy, HIV-1 eradication has been considered as an additional strategy to help fight the AIDS epidemic. With the support of multiple funding agencies, research groups worldwide have been developing protocols to achieve either a sterilizing or a functional cure for HIV-infection.

Recent Findings

Most of the studies focus on the elimination or suppression of circulating CD4+ T cells, the best characterized HIV-1 latent reservoir. The role of the central nervous system (CNS) as a latent reservoir is still controversial. Although brain macrophages and astrocytes are susceptible to HIV-1 infection, it has not been ascertained whether the CNS carries latent HIV-1 during cART and, if so, whether the virus can be reactivated and spread to other compartments after ART interruption.

Summary

Here, we examine the implications of HIV-1 eradication strategies on the CNS, regardless of whether it is a true latent reservoir and, if so, whether it is present in all patients.

Keywords

HIV latency CNS HIV cure 

Notes

Compliance with Ethical Standards

Conflict of Interest

Dr. Veenhuis and Dr. Clements declare no conflicts of interest. Dr. Gama reports grants from NIH, during the conduct of the study.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    CDC. Centers for Disease Control and Prevention Report - More people with HIV have the virus under control 2017. Available from: https://www.cdc.gov/nchhstp/newsroom/2017/2017-HIV-Continuum-Press-Release.html. Accessed 1 Aug 2018.
  2. 2.
    UNAIDS. 2017 Global HIV Statistics 2018. Available from: http://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf. Accessed 1 Aug 2018.
  3. 3.
    Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol. 2008;214(2):231–41.  https://doi.org/10.1002/path.2276.Google Scholar
  4. 4.
    Kamat A, Misra V, Cassol E, Ancuta P, Yan Z, Li C, et al. A plasma biomarker signature of immune activation in HIV patients on antiretroviral therapy. PLoS One. 2012;7(2):e30881.  https://doi.org/10.1371/journal.pone.0030881.Google Scholar
  5. 5.
    Churchill MJ, Deeks SG, Margolis DM, Siliciano RF, Swanstrom R. HIV reservoirs: what, where and how to target them. Nat Rev Microbiol. 2016;14(1):55–60.  https://doi.org/10.1038/nrmicro.2015.5.Google Scholar
  6. 6.
    Siliciano JD, Siliciano RF. The latent reservoir for HIV-1 in resting CD4+ T cells: a barrier to cure. Curr Opin HIV AIDS. 2006;1(2):121–8.  https://doi.org/10.1097/01.COH.0000209582.82328.b8.Google Scholar
  7. 7.
    Churchill M, Nath A. Where does HIV hide? A focus on the central nervous system. Curr Opin HIV AIDS. 2013;8(3):165–9.Google Scholar
  8. 8.•
    Gama L, Abreu CM, Shirk EN, Price SL, Li M, Laird GM, et al. Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques. AIDS. 2017;31(1):5–14. This was the first paper to show that the CNS harbors latent SIV genomes that can be reactivated by LRAs causing increased inflammation and activation in the brain and CSF.Google Scholar
  9. 9.
    Avalos CR, Abreu CM, Queen SE, Li M, Price S, Shirk EN, et al. Brain Macrophages in simian immunodeficiency virus-infected, antiretroviral-suppressed macaques: a functional latent reservoir. MBio. 2017;8(4).  https://doi.org/10.1128/mBio.01186-17
  10. 10.
    Marban C, Forouzanfar F, Ait-Ammar A, Fahmi F, El Mekdad H, Daouad F, et al. Targeting the brain reservoirs: toward an HIV cure. Front Immunol. 2016;7:397.Google Scholar
  11. 11.
    Simioni S, Cavassini M, Annoni JM, Rimbault Abraham A, Bourquin I, Schiffer V, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS. 2010;24(9):1243–50.  https://doi.org/10.1097/QAD.0b013e3283354a7b.Google Scholar
  12. 12.
    Zayyad Z, Spudich S. Neuropathogenesis of HIV: from initial neuroinvasion to HIV-associated neurocognitive disorder (HAND). Curr HIV/AIDS Rep. 2015;12(1):16–24.  https://doi.org/10.1007/s11904-014-0255-3.Google Scholar
  13. 13.
    Vivithanaporn P, Heo G, Gamble J, Krentz HB, Hoke A, Gill MJ, et al. Neurologic disease burden in treated HIV/AIDS predicts survival: a population-based study. Neurology. 2010;75(13):1150–8.  https://doi.org/10.1212/WNL.0b013e3181f4d5bb.Google Scholar
  14. 14.
    Gelman BB, Lisinicchia JG, Morgello S, Masliah E, Commins D, Achim CL, et al. Neurovirological correlation with HIV-associated neurocognitive disorders and encephalitis in a HAART-era cohort. J Acquir Immune Defic Syndr. 2013;62(5):487–95.  https://doi.org/10.1097/QAI.0b013e31827f1bdb.Google Scholar
  15. 15.
    Hassett JM, Zaroulis CG, Greenberg ML, Siegal FP. Bone marrow transplantation in AIDS. N Engl J Med. 1983;309(11):665.  https://doi.org/10.1056/NEJM198309153091114.Google Scholar
  16. 16.
    Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360(7):692–8.  https://doi.org/10.1056/NEJMoa0802905.Google Scholar
  17. 17.
    Lederman MM, Cannon PM, Currier JS, June CH, Kiem HP, Kuritzkes DR, et al. A cure for HIV infection: “Not in My Lifetime” or “Just Around the Corner”? Pathog Immun. 2016;1(1):154–64.  https://doi.org/10.20411/pai.v1i1.133.Google Scholar
  18. 18.
    Dinoso JB, Kim SY, Wiegand AM, Palmer SE, Gange SJ, Cranmer L, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 2009;106(23):9403–8.  https://doi.org/10.1073/pnas.0903107106.Google Scholar
  19. 19.
    Rasmussen TA, McMahon JH, Chang JJ, Audsley J, Rhodes A, Tennakoon S, et al. The effect of antiretroviral intensification with dolutegravir on residual virus replication in HIV-infected individuals: a randomised, placebo-controlled, double-blind trial. Lancet HIV. 2018;5(5):e221–e30.  https://doi.org/10.1016/S2352-3018(18)30040-7.Google Scholar
  20. 20.
    Kim CJ, Rousseau R, Huibner S, Kovacs C, Benko E, Shahabi K, et al. Impact of intensified antiretroviral therapy during early HIV infection on gut immunology and inflammatory blood biomarkers. AIDS. 2017;31(11):1529–34.  https://doi.org/10.1097/QAD.0000000000001515.Google Scholar
  21. 21.
    Somboonwit C, Montero JA, Sinnott JT, Shapshak P. Antiretroviral therapy: brain penetration. Global Virology II – HIV and Neuro AIDS. New York: Springer, 2017. p. 405–34.Google Scholar
  22. 22.
    Decloedt EH, Rosenkranz B, Maartens G, Joska J. Central nervous system penetration of antiretroviral drugs: pharmacokinetic, pharmacodynamic and pharmacogenomic considerations. Clin Pharmacokinet. 2015;54(6):581–98.  https://doi.org/10.1007/s40262-015-0257-3.Google Scholar
  23. 23.
    Letendre SL, Mills AM, Tashima KT, Thomas DA, Min SS, Chen S, et al. ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects. Clin Infect Dis. 2014;59(7):1032–7.  https://doi.org/10.1093/cid/ciu477.Google Scholar
  24. 24.
    Scheper H, van Holten N, Hovens J, de Boer M. Severe depression as a neuropsychiatric side effect induced by dolutegravir. HIV Med. 2018;19(4):e58–e9.  https://doi.org/10.1111/hiv.12538.Google Scholar
  25. 25.
    Zash R, Makhema J, Shapiro RL. Neural-tube defects with dolutegravir treatment from the time of conception. N Engl J Med. 2018;379(10):979–81.  https://doi.org/10.1056/NEJMc1807653.Google Scholar
  26. 26.
    Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278(5341):1295–300.Google Scholar
  27. 27.
    Flad HD, Ernst M, Kern P. A phase I/II trial of recombinant interleukin-2 in AIDS/ARC: alterations of phenotypes of peripheral blood mononuclear cells. Lymphokine Res. 1986;5(Suppl 1):S171–6.Google Scholar
  28. 28.
    Marwick C. Interleukin 2 trial will try to spark flagging immunity of AIDS patients. JAMA. 1983;250(9):1125.Google Scholar
  29. 29.
    Chun TW, Engel D, Mizell SB, Ehler LA, Fauci AS. Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. J Exp Med. 1998;188(1):83–91.Google Scholar
  30. 30.
    Deeks SG. HIV: Shock and kill. Nature. 2012;487(7408):439–40.  https://doi.org/10.1038/487439a.Google Scholar
  31. 31.
    Prins JM, Jurriaans S, van Praag RM, Blaak H, van Rij R, Schellekens PT, et al. Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS. 1999;13(17):2405–10.Google Scholar
  32. 32.
    Chun TW, Engel D, Mizell SB, Hallahan CW, Fischette M, Park S, et al. Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nat Med. 1999;5(6):651–5.  https://doi.org/10.1038/9498.Google Scholar
  33. 33.
    Guirguis LM, Yang JC, White DE, Steinberg SM, Liewehr DJ, Rosenberg SA, et al. Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases. J Immunother. 2002;25(1):82–7.Google Scholar
  34. 34.
    Hurst R, White DE, Heiss J, Lee DS, Rosenberg SA, Schwartzentruber DJ. Brain metastasis after immunotherapy in patients with metastatic melanoma or renal cell cancer: is craniotomy indicated? J Immunother. 1999;22(4):356–62.Google Scholar
  35. 35.
    Burrack KS, Huggins MA, Taras E, Dougherty P, Henzler CM, Yang R, et al. Interleukin-15 complex treatment protects mice from cerebral malaria by inducing interleukin-10-producing natural killer cells. Immunity. 2018;48(4):760–72 e4.  https://doi.org/10.1016/j.immuni.2018.03.012.Google Scholar
  36. 36.
    Pan W, Wu X, He Y, Hsuchou H, Huang EY, Mishra PK, et al. Brain interleukin-15 in neuroinflammation and behavior. Neurosci Biobehav Rev. 2013;37(2):184–92.  https://doi.org/10.1016/j.neubiorev.2012.11.009.Google Scholar
  37. 37.
    Romee R, Cooley S, Berrien-Elliott MM, Westervelt P, Verneris MR, Wagner JE, et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood. 2018;131(23):2515–27.  https://doi.org/10.1182/blood-2017-12-823,757.Google Scholar
  38. 38.
    Broux B, Mizee MR, Vanheusden M, van der Pol S, van Horssen J, Van Wijmeersch B, et al. IL-15 amplifies the pathogenic properties of CD4+CD28- T cells in multiple sclerosis. J Immunol. 2015;194(5):2099–109.  https://doi.org/10.4049/jimmunol.1401547.Google Scholar
  39. 39.
    Subramanian S, Bates SE, Wright JJ, Espinoza-Delgado I, Piekarz RL. Clinical toxicities of histone deacetylase inhibitors. Pharmaceuticals (Basel). 2010;3(9):2751–67.  https://doi.org/10.3390/ph3,092,751.Google Scholar
  40. 40.
    Woyach JA, Kloos RT, Ringel MD, Arbogast D, Collamore M, Zwiebel JA, et al. Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma. J Clin Endocrinol Metab. 2009;94(1):164–70.  https://doi.org/10.1210/jc.2008-1631.Google Scholar
  41. 41.
    Kadia TM, Yang H, Ferrajoli A, Maddipotti S, Schroeder C, Madden TL, et al. A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukemia. Br J Haematol. 2010;150(1):72–82.  https://doi.org/10.1111/j.1365-2141.2010.08211.x.Google Scholar
  42. 42.
    Yang SS, Zhang R, Wang G, Zhang YF. The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer’s disease. Transl Neurodegener. 2017;6:19.  https://doi.org/10.1186/s40035-017-0089-1.Google Scholar
  43. 43.
    Dental C, Proust A, Ouellet M, Barat C, Tremblay MJ. HIV-1 Latency-reversing agents prostratin and bryostatin-1 induce blood-brain barrier disruption/inflammation and modulate leukocyte adhesion/transmigration. J Immunol. 2017;198(3):1229–41.  https://doi.org/10.4049/jimmunol.1600742.Google Scholar
  44. 44.
    Proust A, Barat C, Leboeuf M, Drouin J, Tremblay MJ. Contrasting effect of the latency-reversing agents bryostatin-1 and JQ1 on astrocyte-mediated neuroinflammation and brain neutrophil invasion. J Neuroinflammation. 2017;14(1):242.  https://doi.org/10.1186/s12974-017-1019-y.Google Scholar
  45. 45.
    Sun MK, Alkon DL. Bryostatin-1: pharmacology and therapeutic potential as a CNS drug. CNS Drug Rev. 2006;12(1):1–8.  https://doi.org/10.1111/j.1527-3458.2006.00001.x.Google Scholar
  46. 46.
    Honda Y, Rogers L, Nakata K, Zhao BY, Pine R, Nakai Y, et al. Type I interferon induces inhibitory 16-kD CCAAT/enhancer binding protein (C/EBP) beta, repressing the HIV-1 long terminal repeat in macrophages: Pulmonary tuberculosis alters C/EBP expression, enhancing HIV-1 replication. J Exp Med. 1998;188(7):1255–65.  https://doi.org/10.1084/Jem.188.7.1255.Google Scholar
  47. 47.
    Barber SA, Gama L, Dudaronek JM, Voelker T, Tarwater PM, Clements JE. Mechanism for the establishment of transcriptional HIV latency in the brain in a simian immunodeficiency virus-macaque model. J Infect Dis. 2006;193(7):963–70.  https://doi.org/10.1086/500983.Google Scholar
  48. 48.
    Eneanya DI, Bianchine JR, Duran DO, Andresen BD. The actions of metabolic fate of disulfiram. Annu Rev Pharmacol Toxicol. 1981;21:575–96.  https://doi.org/10.1146/annurev.pa.21.040181.003043.Google Scholar
  49. 49.
    Gray LR, On H, Roberts E, Lu HK, Moso MA, Raison JA, et al. Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells. J Neuro-Oncol. 2016;22(4):455–63.  https://doi.org/10.1007/s13365-015-0413-4.Google Scholar
  50. 50.
    Gavegnano C, Schinazi RF. Antiretroviral therapy in macrophages: implication for HIV eradication. Antivir Chem Chemother. 2009;20(2):63–78.  https://doi.org/10.3851/IMP1374.Google Scholar
  51. 51.
    Gray LR, Tachedjian G, Ellett AM, Roche MJ, Cheng WJ, Guillemin GJ, et al. The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes. PLoS One. 2013;8(4):e62196.  https://doi.org/10.1371/journal.pone.0062196.Google Scholar
  52. 52.
    Sami Saribas A, Cicalese S, Ahooyi TM, Khalili K, Amini S, Sariyer IK. HIV-1 Nef is released in extracellular vesicles derived from astrocytes: evidence for Nef-mediated neurotoxicity. Cell Death Dis. 2017;8(1):e2542.  https://doi.org/10.1038/cddis.2016.467.Google Scholar
  53. 53.
    van Marle G, Henry S, Todoruk T, Sullivan A, Silva C, Rourke SB, et al. Human immunodeficiency virus type 1 Nef protein mediates neural cell death: a neurotoxic role for IP-10. Virology. 2004;329(2):302–18.  https://doi.org/10.1016/j.virol.2004.08.024.Google Scholar
  54. 54.
    King JE, Eugenin EA, Buckner CM, Berman JW. HIV tat and neurotoxicity. Microbes Infect. 2006;8(5):1347–57.  https://doi.org/10.1016/j.micinf.2005.11.014.Google Scholar
  55. 55.
    Li W, Li G, Steiner J, Nath A. Role of Tat protein in HIV neuropathogenesis. Neurotox Res. 2009;16(3):205–20.  https://doi.org/10.1007/s12640-009-9047-8.Google Scholar
  56. 56.
    Danaher RJ, Jacob RJ, Steiner MR, Allen WR, Hill JM, Miller CS. Histone deacetylase inhibitors induce reactivation of herpes simplex virus type 1 in a latency-associated transcript-independent manner in neuronal cells. J Neuro-Oncol. 2005;11(3):306–17.  https://doi.org/10.1080/13550280590952817.Google Scholar
  57. 57.
    Krishna BA, Lau B, Jackson SE, Wills MR, Sinclair JH, Poole E. Transient activation of human cytomegalovirus lytic gene expression during latency allows cytotoxic T cell killing of latently infected cells. Sci Rep. 2016;6:24674.  https://doi.org/10.1038/srep24674.Google Scholar
  58. 58.
    Gradoville L, Kwa D, El-Guindy A, Miller G. Protein kinase C-independent activation of the Epstein-Barr virus lytic cycle. J Virol. 2002;76(11):5612–26.Google Scholar
  59. 59.
    Lopalco L. CCR5: from natural resistance to a new anti-HIV strategy. Viruses. 2010;2(2):574–600.  https://doi.org/10.3390/v2020574.Google Scholar
  60. 60.
    Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S, Lee TH, et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med. 2014;161(5):319–27.  https://doi.org/10.7326/M14-1027.Google Scholar
  61. 61.
    Verheyen J, Thielen A, Lubke N, Dirks M, Widera M, Dittmer U, et al. Rapid rebound of a preexisting CXCR4-tropic HIV variant after allogeneic transplantation with CCR5 delta32 homozygous stem cells. Clin Infect Dis. 2018.  https://doi.org/10.1093/cid/ciy565.
  62. 62.
    Yoshida S, Hayakawa K, Yamamoto A, Kuroda H, Imashuku S. The central nervous system complications of bone marrow transplantation in children. Eur Radiol. 2008;18(10):2048–59.  https://doi.org/10.1007/s00330-008-1000-3.Google Scholar
  63. 63.
    Grauer O, Wolff D, Bertz H, Greinix H, Kuhl JS, Lawitschka A, et al. Neurological manifestations of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graft-versus-host disease. Brain. 2010;133(10):2852–65.  https://doi.org/10.1093/brain/awq245.Google Scholar
  64. 64.
    Pruitt AA, Graus F, Rosenfeld MR. Neurological complications of transplantation: part I: hematopoietic cell transplantation. Neurohospitalist. 2013;3(1):24–38.  https://doi.org/10.1177/1941874412455338.Google Scholar
  65. 65.
    Lee H, Narayanan S, Brown RA, Chen JT, Atkins HL, Freedman MS, et al. Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis. Mult Scler. 2017;23(3):420–31.  https://doi.org/10.1177/1352458516650992.Google Scholar
  66. 66.
    Seishima M, Yamanaka S, Fujisawa T, Tohyama M, Hashimoto K. Reactivation of human herpesvirus (HHV) family members other than HHV-6 in drug-induced hypersensitivity syndrome. Br J Dermatol. 2006;155(2):344–9.  https://doi.org/10.1111/j.1365-2133.2006.07332.x.Google Scholar
  67. 67.
    Fricker-Hidalgo H, Bulabois CE, Brenier-Pinchart MP, Hamidfar R, Garban F, Brion JP, et al. Diagnosis of toxoplasmosis after allogeneic stem cell transplantation: results of DNA detection and serological techniques. Clin Infect Dis. 2009;48(2):e9–e15.  https://doi.org/10.1086/595709.Google Scholar
  68. 68.
    Cannon PM, Kohn DB, Kiem HP. HIV eradication--from Berlin to Boston. Nat Biotechnol. 2014;32(4):315–6.  https://doi.org/10.1038/nbt.2868.Google Scholar
  69. 69.
    Larochelle A, Bellavance MA, Michaud JP, Rivest S. Bone marrow-derived macrophages and the CNS: An update on the use of experimental chimeric mouse models and bone marrow transplantation in neurological disorders. Biochim Biophys Acta. 2016;1862(3):310–22.  https://doi.org/10.1016/j.bbadis.2015.09.017.Google Scholar
  70. 70.
    Euler Z, Alter G. Exploring the potential of monoclonal antibody therapeutics for HIV-1 eradication. AIDS Res Hum Retrovir. 2015;31(1):13–24.  https://doi.org/10.1089/AID.2014.0235.Google Scholar
  71. 71.
    Chun TW, Murray D, Justement JS, Blazkova J, Hallahan CW, Fankuchen O, et al. Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir. Proc Natl Acad Sci U S A. 2014;111(36):13151–6.  https://doi.org/10.1073/pnas.1414148111.Google Scholar
  72. 72.
    Rubenstein JL, Combs D, Rosenberg J, Levy A, McDermott M, Damon L, et al. Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood. 2003;101(2):466–8.  https://doi.org/10.1182/blood-2002-06-1636.Google Scholar
  73. 73.•
    Stefic K, Chaillon A, Bouvin-Pley M, Moreau A, Braibant M, Bastides F, et al. Probing the compartmentalization of HIV-1 in the central nervous system through its neutralization properties. PLoS One. 2017;12(8):e0181680.  https://doi.org/10.1371/journal.pone.0181680. This paper demonstrated that virus isolated from the CNS may be resistant to neutralizing antibodies that otherwise work on viruses isolated from plasma, suggesting that HIV-1 broadly neutralizing antibodies may be poorly effective to eradicate reservoirs in the CNS.
  74. 74.
    Velu V, Shetty RD, Larsson M, Shankar EM. Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options. Retrovirology. 2015;12:14.  https://doi.org/10.1186/s12977-015-0144-x.Google Scholar
  75. 75.
    Olesen R, Leth S, Nymann R, Ostergaard L, Sogaard OS, Denton PW, et al. Immune checkpoints and the HIV-1 reservoir: proceed with caution. J Virus Erad. 2016;2(3):183–6.Google Scholar
  76. 76.
    Dudnik E, Yust-Katz S, Nechushtan H, Goldstein DA, Zer A, Flex D, et al. Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases. Lung Cancer. 2016;98:114–7.  https://doi.org/10.1016/j.lungcan.2016.05.031.Google Scholar
  77. 77.
    Hung AL, Maxwell R, Theodros D, Belcaid Z, Mathios D, Luksik AS, et al. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. OncoImmunology. 2018;7:e1466769.  https://doi.org/10.1080/2162402X.2018.1466769.Google Scholar
  78. 78.
    Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26(12):2375–91.  https://doi.org/10.1093/annonc/mdv383.Google Scholar
  79. 79.
    Mousseau G, Clementz MA, Bakeman WN, Nagarsheth N, Cameron M, Shi J, et al. An analog of the natural steroidal alkaloid cortistatin A potently suppresses Tat-dependent HIV transcription. Cell Host Microbe. 2012;12(1):97–108.  https://doi.org/10.1016/j.chom.2012.05.016.Google Scholar
  80. 80.•
    Kessing CF, Nixon CC, Li C, Tsai P, Takata H, Mousseau G, et al. In vivo suppression of HIV rebound by didehydro-cortistatin A, a “block-and-lock” strategy for HIV-1 treatment. Cell Rep. 2017;21(3):600–11.  https://doi.org/10.1016/j.celrep.2017.09.080. This paper showed that the compound used to "block and lock" the genome was able to cross the blood brain barrier in mice and significantly reduce HIV RNA levels in the brain and decrease neuroinflammation caused by viral proteins, such as Tat and Nef. These data suggest this method may be a viable option for reducing the functional reservoir in the CNS.
  81. 81.
    Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011;472(7344):481–5.  https://doi.org/10.1038/nature09907.Google Scholar
  82. 82.
    Rijckborst V, Janssen HL. The role of interferon in hepatitis B therapy. Curr Hepat Rep. 2010;9(4):231–8.  https://doi.org/10.1007/s11901-010-0055-1.Google Scholar
  83. 83.
    Rong L, Perelson AS. Treatment of hepatitis C virus infection with interferon and small molecule direct antivirals: viral kinetics and modeling. Crit Rev Immunol. 2010;30(2):131–48.Google Scholar
  84. 84.
    Festi D, Sandri L, Mazzella G, Roda E, Sacco T, Staniscia T, et al. Safety of interferon beta treatment for chronic HCV hepatitis. World J Gastroenterol. 2004;10(1):12–6.Google Scholar
  85. 85.
    Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19(2):105–23.Google Scholar
  86. 86.
    Antonucci JM, St Gelais C, Wu L. The dynamic interplay between HIV-1, SAMHD1, and the innate antiviral response. Front Immunol. 2017;8:1541.  https://doi.org/10.3389/fimmu.2017.01541.Google Scholar
  87. 87.
    Kane M, Zang TM, Rihn SJ, Zhang F, Kueck T, Alim M, et al. Identification of interferon-stimulated genes with antiretroviral activity. Cell Host Microbe. 2016;20(3):392–405.  https://doi.org/10.1016/j.chom.2016.08.005.Google Scholar
  88. 88.
    Azzoni L, Foulkes AS, Papasavvas E, Mexas AM, Lynn KM, Mounzer K, et al. Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. J Infect Dis. 2013;207(2):213–22.  https://doi.org/10.1093/infdis/jis663.Google Scholar
  89. 89.
    Moron-Lopez S, Gomez-Mora E, Salgado M, Ouchi D, Puertas MC, Urrea V, et al. Short-term treatment with interferon alfa diminishes expression of HIV-1 and reduces CD4+ T Cell activation in patients coinfected with HIV and hepatitis C virus and receiving antiretroviral therapy. J Infect Dis. 2016;213(6):1008–12.  https://doi.org/10.1093/infdis/jiv521.Google Scholar
  90. 90.
    Fritz-French C, Tyor W. Interferon-alpha (IFNalpha) neurotoxicity. Cytokine Growth Factor Rev. 2012;23(1–2):7–14.  https://doi.org/10.1016/j.cytogfr.2012.01.001.Google Scholar
  91. 91.
    Meyers CA, Scheibel RS, Forman AD. Persistent neurotoxicity of systemically administered interferon-alpha. Neurology. 1991;41(5):672–6.Google Scholar
  92. 92.
    Witwer KW, Gama L, Li M, Bartizal CM, Queen SE, Varrone JJ, et al. Coordinated regulation of SIV replication and immune responses in the CNS. PLoS One. 2009;4(12):e8129.  https://doi.org/10.1371/journal.pone.0008129.Google Scholar
  93. 93.
    Alammar L, Gama L, Clements JE. Simian immunodeficiency virus infection in the brain and lung leads to differential type I IFN signaling during acute infection. J Immunol. 2011;186(7):4008–18.  https://doi.org/10.4049/jimmunol.1003757.Google Scholar
  94. 94.
    Meyers CA, Obbens EA, Scheibel RS, Moser RP. Neurotoxicity of intraventricularly administered alpha-interferon for leptomeningeal disease. Cancer. 1991;68(1):88–92.Google Scholar
  95. 95.
    Adams F, Fernandez F, Mavligit G. Interferon-induced organic mental disorders associated with unsuspected pre-existing neurologic abnormalities. J Neuro-Oncol. 1988;6(4):355–9.Google Scholar
  96. 96.
    Renault PF, Hoofnagle JH, Park Y, Mullen KD, Peters M, Jones DB, et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med. 1987;147(9):1577–80.Google Scholar
  97. 97.
    Alavi M, Grebely J, Matthews GV, Petoumenos K, Yeung B, Day C, et al. Effect of pegylated interferon-alpha-2a treatment on mental health during recent hepatitis C virus infection. J Gastroenterol Hepatol. 2012;27(5):957–65.  https://doi.org/10.1111/j.1440-1746.2011.07035.x.Google Scholar
  98. 98.
    Clinicaltrials.gov. Clinical trials using interferon in the context of HIV-1 infection 2018. Available from: https://clinicaltrials.gov/ct2/results?cond=HIV&term=IFN&cntry=&state=&city=&dist=. Accessed 1 Aug 2018.
  99. 99.
    Benjamin R, Berges BK, Solis-Leal A, Igbinedion O, Strong CL, Schiller MR. TALEN gene editing takes aim on HIV. Hum Genet. 2016;135(9):1059–70.  https://doi.org/10.1007/s00439-016-1678-2.Google Scholar
  100. 100.
    Liu Z, Chen S, Jin X, Wang Q, Yang K, Li C, et al. Genome editing of the HIV co-receptors CCR5 and CXCR4 by CRISPR-Cas9 protects CD4(+) T cells from HIV-1 infection. Cell Biosci. 2017;7:47.  https://doi.org/10.1186/s13578-017-0174-2.Google Scholar
  101. 101.
    Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370(10):901–10.  https://doi.org/10.1056/NEJMoa1300662.Google Scholar
  102. 102.
    Zahur M, Tolo J, Bahr M, Kugler S. Long-term assessment of AAV-mediated zinc finger nuclease expression in the mouse brain. Front Mol Neurosci. 2017;10:142.  https://doi.org/10.3389/fnmol.2017.00142.Google Scholar
  103. 103.
    Huang Z, Nair M. A CRISPR/Cas9 guidance RNA screen platform for HIV provirus disruption and HIV/AIDS gene therapy in astrocytes. Sci Rep. 2017;7(1):5955.  https://doi.org/10.1038/s41598-017-06269-x.Google Scholar
  104. 104.
    Hu W, Kaminski R, Yang F, Zhang Y, Cosentino L, Li F, et al. RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection. Proc Natl Acad Sci U S A. 2014;111(31):11461–6.  https://doi.org/10.1073/pnas.1405186111.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Rebecca T. Veenhuis
    • 1
  • Janice E. Clements
    • 1
  • Lucio Gama
    • 1
    • 2
    Email author
  1. 1.Department of Molecular and Comparative PathobiologyJohns Hopkins School of MedicineBaltimoreUSA
  2. 2.Vaccine Research Center – NIAID – NIHBethesdaUSA

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