Skip to main content

Advertisement

SpringerLink
Log in

Immunotherapeutics to Treat HIV in the Central Nervous System

  • Central Nervous System and Cognition (SS Spudich, Section Editor)
  • Published:
Current HIV/AIDS Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The application of immunotherapies to HIV presents a new horizon of treatment options, but little is known about what impact they may have on the central nervous system (CNS). Here we review the most promising immunotherapeutic strategies that can be used to target HIV in the CNS and focus on identifying their potential benefits while exploring the challenges that remain in their application.

Recent Findings

We have identified five immunotherapeutic strategies that hold potential in managing CNS disease among HIV-infected patients. These include broadly neutralizing antibodies, multi-affinity antibodies, CAR-T cell therapy, checkpoint inhibitors, and therapeutic vaccines.

Summary

Each class of immunotherapy presents unique mechanisms by which CNS viremia and latency may be addressed but are faced with several challenges. CAR-T cell therapy and multi-affinity antibodies seem to hold promise, but combination therapy is likely to be most effective. However, more human trials are needed before the clinical benefits of these therapies are realized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Routy JP, Mehraj V, Cao W. HIV immunotherapy comes of age: implications for prevention, treatment and cure. Expert Rev Clin Immunol. 2016;12:91–4.

    PubMed  CAS  Google Scholar 

  2. Nachega JB, Marconi VC, van Zyl GU, Gardner EM, Preiser W, Hong SY, et al. HIV treatment adherence, drug resistance, virologic failure: evolving concepts. Infect Disord Drug Targets. 2011;11:167–74.

    PubMed  PubMed Central  CAS  Google Scholar 

  3. Chun TW, Moir S, Fauci AS. HIV reservoirs as obstacles and opportunities for an HIV cure. Nat Immunol. 2015;16:584–9.

    PubMed  CAS  Google Scholar 

  4. 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.

  5. Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65:65–70.

    PubMed  PubMed Central  Google Scholar 

  6. Caniglia EC, Cain LE, Justice A, Tate J, Logan R, Sabin C, et al. Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions. Neurol Lippincott Williams Wilkins. 2014;83:134–41.

    Google Scholar 

  7. •• Canestri A, Lescure F, Jaureguiberry S, Moulignier A, Amiel C, Marcelin AG, et al. Discordance Between Cerebral Spinal Fluid and Plasma HIV Replication in Patients with Neurological Symptoms Who Are Receiving Suppressive Antiretroviral Therapy. Clin Infect Dis. 2010;50:773–8 Oxford University Press. This study demonstrated detectable HIV DNA in the CSF of half of patients with HIV who were suppressed with undetectable peripheral viral loads on long term ART.

    PubMed  Google Scholar 

  8. Spudich S, Robertson KR, Bosch RJ, Gandhi RT, Cyktor JC, Mar H, et al. Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance. J Clin Invest. American Society for Clinical Investigation. 2019;129:3339–46.

    PubMed  PubMed Central  Google Scholar 

  9. Valcour V, Sithinamsuwan P, Letendre S, Ances B. Pathogenesis of HIV in the central nervous system. Curr HIV/AIDS Rep. 2011;8(1)54–61.

  10. Gray LR, Roche M, Flynn JK, Wesselingh SL, Gorry PR, Churchill MJ. Is the central nervous system a reservoir of HIV-1? Curr Opin HIV AIDS. 2014;9:552–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  11. Churchill M, Nath A. Where does HIV hide? A focus on the central nervous system. Curr Opin HIV AIDS. 2013;8(3):165–9.

  12. Hellmuth J, Valcour V, Spudich S. CNS reservoirs for HIV: implications for eradication. J Virus Erad. 2015;1:67–71.

    PubMed  PubMed Central  Google Scholar 

  13. Joseph SB, Arrildt KT, Sturdevant CB, Swanstrom R. HIV-1 target cells in the CNS. J Neurovirol Springer New York LLC. 2015;21:276–89.

    CAS  Google Scholar 

  14. Muldoon LL, Alvarez JI, Begley DJ, Boado RJ, Del Zoppo GJ, Doolittle ND, et al. Immunologic privilege in the central nervous system and the blood-brain barrier. J Cereb Blood Flow Metab. 2013;33:13–21.

    PubMed  CAS  Google Scholar 

  15. Yilmaz A, Price RW, Gisslén M. Antiretroviral drug treatment of CNS HIV-1 infection. J Antimicrob Chemother. 2012;67(2):299–311.

  16. Halper-Stromberg A, Nussenzweig MC. Towards HIV-1 remission: Potential roles for broadly neutralizing antibodies. J Clin Invest. 2016;126(2):415–23.

  17. Gama L, Koup RA. New-generation high-potency and designer antibodies: role in HIV-1 treatment. Annu Rev Med Ann Rev. 2018;69:409–19.

    CAS  Google Scholar 

  18. Barouch DH, Whitney JB, Moldt B, Klein F, Oliveira TY, Liu J, et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature. 2013;503:224–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  19. Emu B, Fessel J, Schrader S, Kumar P, Richmond G, Win S, et al. Phase 3 study of Ibalizumab for multidrug-resistant HIV-1. N Engl J Med. 2018;379:645–54.

    PubMed  CAS  Google Scholar 

  20. Caskey M, Klein F, Lorenzi JCC, Seaman MS, West AP, Buckley N, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature Nature Publ Group. 2015;522:487–91.

    CAS  Google Scholar 

  21. Bar-On Y, Gruell H, Schoofs T, Pai JA, Nogueira L, Butler AL, et al. Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals. Nat Med. 2018;24:1701–7.

    PubMed  PubMed Central  CAS  Google Scholar 

  22. Veenhuis RT, Clements JE, Gama L. HIV Eradication Strategies: Implications for the Central Nervous System. Curr HIV/AIDS Rep. Current Medicine Group LLC 1. 2019;16(1):96–104.

  23. •• Rubenstein JL, Combs D, Rosenberg J, Levy A, McDermott M, Damon L, et al. Rituximab therapy for CNS lymphomas: Targeting the leptomeningeal compartment. Blood, The Journal of the American Society of Hematology 2003;101(2):466–8. This study demonstrated the poor CNS penetration of rituximab - a human monoclonal antibody.

  24. Hessell AJ, Jaworski JP, Epson E, Matsuda K, Pandey S, Kahl C, et al. Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques. Nat Med. Nature Publishing Group. 2016;22:362–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  25. Khan SN, Sok D, Tran K, Movsesyan A, Dubrovskaya V, Burton DR, et al. Targeting the HIV-1 spike and coreceptor with bi- and trispecific antibodies for single-component broad inhibition of entry. J Virol Am Soc Microbiol. 2018;92(18).

  26. Margolis DM, Garcia JV, Ph D. Countering HIV-Three’s the charm? N Engl J Med. 2018;378:295–7.

    PubMed  Google Scholar 

  27. Steinhardt JJ, Guenaga J, Turner HL, McKee K, Louder MK, O’Dell S, et al. Rational design of a trispecific antibody targeting the HIV-1 Env with elevated anti-viral activity. Nat Commun. Nature Publishing Group. 2018;9.

  28. Padte NN, Yu J, Huang Y, Ho DD. Engineering multi-specific antibodies against HIV-1. Retrovirology. 2018;15:60.

    PubMed  PubMed Central  Google Scholar 

  29. Cohen YZ, Caskey M. Broadly neutralizing antibodies for treatment and prevention of HIV-1 infection. Curr Opin HIV AIDS, Lippincott Williams Wilkins. 2018;13(4):366–73.

  30. Grobben M, Stuart RAL, van Gils MJ. The potential of engineered antibodies for HIV-1 therapy and cure. Curr Opin Virol. Elsevier B.V. 2019;38:70–80.

  31. Xu L, Pegu A, Rao E, Doria-Rose N, Beninga J, McKee K, et al. Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques. Science. 2017;358:85–90.

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Crunkhorn S. HIV: Trispecific antibodies block infection. Nat Rev Drug Discov. 2017;16:754.

    PubMed  Google Scholar 

  33. Yu YJ, Atwal JK, Zhang Y, Tong RK, Wildsmith KR, Tan C, et al. Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates. Sci Transl Med. 2014;66(261):261ra154.

  34. Yang OO, Tran AC, Kalams SA, Johnson RP, Roberts MR, Walker BD. Lysis of HIV-1-infected cells and inhibition of viral replication by universal receptor T cells. Proc Natl Acad Sci. 1997;94:11478–83.

    PubMed  CAS  Google Scholar 

  35. Mylvaganam G, Yanez AG, Maus M, Walker BD. Toward T cell-mediated control or elimination of HIV reservoirs: lessons from cancer immunology. Front Immunol. 2019;10:2109.

    PubMed  PubMed Central  CAS  Google Scholar 

  36. Liu B, Zhang W, Zhang H. Development of CAR-T cells for long-term eradication and surveillance of HIV-1 reservoir. Curr Opin Virol. 2019;38:21–30.

    PubMed  CAS  Google Scholar 

  37. Huyghe J, Magdalena S, Vandekerckhove L. Fight fire with fire: gene therapy strategies to cure HIV. Expert Rev Anti-Infect Ther. 2017;15:747–58.

    PubMed  CAS  Google Scholar 

  38. Kuhlmann AS, Peterson CW, Kiem HP. Chimeric antigen receptor T-cell approaches to HIV cure. Curr Opin HIV AIDS. 2018;13:446–53.

    PubMed  PubMed Central  CAS  Google Scholar 

  39. Anthony-Gonda K, Bardhi A, Ray A, Flerin N, Li M, Chen W, et al. Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model. Sci Transl Med. 2019;11:504.

    Google Scholar 

  40. Ram DR, Manickam C, Lucar O, Shah SV, Reeves RK. Adaptive NK cell responses in HIV/SIV infections: a roadmap to cell-based therapeutics? J Leukoc Biol. 2019;105:1253–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  41. Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med. 2012;4(132):132ra53.

  42. Wagner TA. Quarter Century of Anti-HIV CAR T Cells. Curr HIV/AIDS Rep. Current Medicine Group LLC 1. 2018;15:147–54.

    PubMed  PubMed Central  Google Scholar 

  43. O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. American Association for the Advancement of Science. 2017;9(399).

  44. Zhen A, Carrillo MA, Kitchen SG. Chimeric antigen receptor engineered stem cells: a novel HIV therapy. Immunotherapy. 2017;9:401–10.

    PubMed  PubMed Central  CAS  Google Scholar 

  45. Hunter BD, Jacobson CA. CAR T-cell associated neurotoxicity: mechanisms, Clinicopathologic correlates, and future directions. JNCI J Natl Cancer Inst. 2019;111:646–54.

    PubMed  Google Scholar 

  46. Taraseviciute A, Gust J, Cameron, Turtle J, Turtle CJ, Org C. Neurotoxicity Associated with CD19-Targeted CAR-T Cell Therapies. CNS Drugs. 2018;32:1091–101.

    PubMed  PubMed Central  Google Scholar 

  47. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics Nat Publ Group. 2016;3:16011.

    CAS  Google Scholar 

  48. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy-assessment and management of toxicities. Nat Rev Clin Oncol Nat Publ Group. 2018;(1):47–62.

  49. Walker BD, Burton DR. Toward an AIDS vaccine. Science. 2008;320(5877):760–4.

  50. Gao Y, McKay PF, Mann JFS. Advances in HIV-1 vaccine development. Viruses. MDPI AG; 2018;10(4):167.

  51. Excler JL, Michael NL. Lessons from HIV-1 vaccine efficacy trials. Curr Opin HIV AIDS. Lippincott Williams and Wilkins. 2016;11(6):607–13.

  52. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361:2209–20.

    PubMed  CAS  Google Scholar 

  53. Stephenson KE. Therapeutic vaccination for HIV: hopes and challenges. Curr Opin HIV AIDS. 2018;13:408–15.

    PubMed  Google Scholar 

  54. Alter G, Barouch D. Immune Correlate-Guided HIV Vaccine Design. Cell Host Microbe Cell Press. 2018;24(1):25–33.

  55. Duerr A, Wasserheit JN, Corey L. HIV Vaccines: New Frontiers in Vaccine Development. Clin Infect Dis. Oxford University Press (OUP). 2006;43:500–11.

    PubMed  CAS  Google Scholar 

  56. Jones RB, Walker BD. HIV-specific CD8 T cells and HIV eradication. J Clin Invest. 2016;126:455–63.

    PubMed  PubMed Central  Google Scholar 

  57. Bournazos S, Ravetch JV. Anti-retroviral antibody FcγR-mediated effector functions. Immunol Rev. Blackwell Publishing Ltd. 2017;275(1):285–95.

  58. Castro-Gonzalez S, Colomer-Lluch M, Serra-Moreno R. Barriers for HIV cure: the latent reservoir. AIDS Res Hum Retrovir. 2018;34:739–59.

    PubMed  Google Scholar 

  59. Spivak AM, Planelles V. Novel latency reversal agents for HIV-1 cure. Annu Rev Med Annual Reviews. 2018;69:421–36.

    CAS  Google Scholar 

  60. Masopust D. Developing an HIV cytotoxic T-lymphocyte vaccine: issues of CD8 T-cell quantity, quality and location. J Intern Med. 2009;265:125–37.

    PubMed  CAS  Google Scholar 

  61. Folkvord JM, Armon C, Connick E. Lymphoid follicles are sites of heightened human immunodeficiency virus type 1 (HIV-1) replication and reduced antiretroviral effector mechanisms. AIDS Res Hum Retrovir. 2005;21:363–70.

    PubMed  CAS  Google Scholar 

  62. Connick E, Mattila T, Folkvord JM, Schlichtemeier R, Meditz AL, Ray MG, et al. CTL fail to accumulate at sites of HIV-1 replication in lymphoid tissue. J Immunol. 2007;178:6975–83.

    PubMed  CAS  Google Scholar 

  63. La-Beck NM, Jean GW, Huynh C, Alzghari SK, Lowe DB. Immune Checkpoint Inhibitors: New Insights and Current Place in Cancer Therapy. Pharmacotherapy. Pharmacotherapy Publications Inc. 2015;35:963–76.

    PubMed  CAS  Google Scholar 

  64. Porichis F, Kaufmann DE. Role of PD-1 in HIV pathogenesis and as target for therapy. Curr HIV/AIDS Rep. 2012;9(1):81–90.

  65. Wightman F, Solomon A, Kumar SS, Urriola N, Gallagher K, Hiener B, et al. Effect of ipilimumab on the HIV reservoir in an HIV-infected individual with metastatic melanoma. AIDS. Lippincott Williams and Wilkins. 2015;29(4):504–6.

  66. Guihot A, Marcelin AG, Massiani MA, Samri A, Soulié C, Autran B, et al. Drastic decrease of the HIV reservoir in a patient treated with nivolumab for lung cancer. Ann Oncol. 2018;29(2):517–8.

  67. Gavegnano C, Savarino A, Owanikoko T, Marconi VC. Crossroads of cancer and HIV-1: pathways to a cure for HIV. Front Immunol. 2019;10:2267.

  68. Cortese I, Muranski P, Enose-Akahata Y, Ha S-K, Smith B, Monaco M, et al. Pembrolizumab treatment for progressive multifocal Leukoencephalopathy. N Engl J Med. 2019;380:1597–605.

    PubMed  CAS  Google Scholar 

  69. Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature. 2009;458:206–10.

    PubMed  CAS  Google Scholar 

  70. Seung E, Dudek TE, Allen TM, Freeman GJ, Luster AD, Tager AM. PD-1 Blockade in Chronically HIV-1-Infected Humanized Mice Suppresses Viral Loads. Apetrei C, editor. PLoS One. 2013;8:77780.

    Google Scholar 

  71. Johnson DB, Manouchehri A, Haugh AM, Quach HT, Balko JM, Lebrun-Vignes B, et al. Neurologic toxicity associated with immune checkpoint inhibitors: A pharmacovigilance study. J Immunother Cancer. 2019;7(1):134.

  72. Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J, et al. Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature. Eur J Cancer. 2017;73:1–8.

  73. •• Dash PK, Kaminski R, Bella R, Su H, Mathews S, Ahooyi TM, et al. Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice. Nat Commun. 2019:10(1):1–20. In this proof of concept study, HIV proviral DNA was removed using genomic editing with CRISPR-Cas19 technology in HIV-1 infected humanized mice.

Download references

Author information

Authors and Affiliations

  1. Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Andrew Kapoor

  2. Division of Infectious Diseases, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue E/CLS 1011, Boston, MA, 02215, USA

    C. Sabrina Tan

Authors
  1. Andrew Kapoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Sabrina Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Sabrina Tan.

Ethics declarations

Conflict of Interest

No potential conflicts of interest relevant to this article were reported.

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Central Nervous System and Cognition

Key Points

- Immunotherapies are needed to address the shortcomings of traditional ART in treating HIV infection in the CNS.

- These immunotherapeutic strategies hold tremendous potential and present unique mechanisms by which CNS viremia and latency may be addressed.

- CAR-T cell therapy and multi-affinity antibodies represent promising areas of immunotherapy with the ability to penetrate the CNS and target latent cells with high specificity.

- More human studies are needed to better understand the potential clinical applications and off target effects these therapies may have specifically in the CNS.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kapoor, A., Tan, C.S. Immunotherapeutics to Treat HIV in the Central Nervous System. Curr HIV/AIDS Rep 17, 499–506 (2020). https://doi.org/10.1007/s11904-020-00519-w

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11904-020-00519-w

Keywords

Search

Navigation