The Use of Toll-Like Receptor Agonists in HIV-1 Cure Strategies

Front Immunol. 2020 Jun 11;11:1112. doi: 10.3389/fimmu.2020.01112. eCollection 2020.


Toll-like receptors (TLRs) are a family of pattern recognition receptors and part of the first line of defense against invading microbes. In humans, we know of 10 different TLRs, which are expressed to varying degrees in immune cell subsets. Engaging TLRs through their specific ligands leads to activation of the innate immune system and secondarily priming of the adaptive immune system. Because of these unique properties, TLR agonists have been investigated as immunotherapy in cancer treatment for many years, but in recent years there has also been growing interest in the use of TLR agonists in the context of human immunodeficiency virus type 1 (HIV-1) cure research. The primary obstacle to curing HIV-1 is the presence of a latent viral reservoir in transcriptionally silent immune cells. Due to the very limited transcription of the integrated HIV-1 proviruses, latently infected cells cannot be targeted and cleared by immune effector mechanisms. TLR agonists are very interesting in this context because of their potential dual effects as latency reverting agents (LRAs) and immune modulatory compounds. Here, we review preclinical and clinical data on the impact of TLR stimulation on HIV-1 latency as well as antiviral and HIV-1-specific immunity. We also focus on the promising role of TLR agonists in combination strategies in HIV-1 cure research. Different combinations of TLR agonists and broadly neutralizing antibodies or TLRs agonists as adjuvants in HIV-1 vaccines have shown very encouraging results in non-human primate experiments and these concepts are now moving into clinical testing.

Keywords: HIV-1; HIV-1 cure; HIV-1 vaccine; TLR; immune modulation; innate immunity; latency reversing agents.

Publication types

  • Review

MeSH terms

  • AIDS Vaccines / administration & dosage
  • Adjuvants, Immunologic / administration & dosage
  • Animals
  • Anti-HIV Agents / pharmacology
  • Broadly Neutralizing Antibodies / administration & dosage
  • Clinical Trials as Topic
  • HIV Antibodies / administration & dosage
  • HIV Infections / immunology*
  • HIV Infections / therapy*
  • HIV-1* / drug effects
  • HIV-1* / immunology
  • HIV-1* / physiology
  • Humans
  • Immune Checkpoint Inhibitors / administration & dosage
  • Immunologic Factors / pharmacology
  • Immunotherapy / methods*
  • In Vitro Techniques
  • Models, Immunological
  • Primates
  • Pteridines / pharmacology
  • Toll-Like Receptor 3 / agonists
  • Toll-Like Receptor 7 / agonists
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptors / agonists*
  • Virus Latency / drug effects
  • Virus Latency / immunology


  • AIDS Vaccines
  • Adjuvants, Immunologic
  • Anti-HIV Agents
  • Broadly Neutralizing Antibodies
  • HIV Antibodies
  • Immune Checkpoint Inhibitors
  • Immunologic Factors
  • Pteridines
  • TLR3 protein, human
  • TLR7 protein, human
  • TLR9 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • vesatolimod