Toll-Like Receptor Agonists: Can They Exact a Toll on Human Immunodeficiency Virus Persistence?

In this issue of Clinical Infectious Diseases, Vibholm et al report on the first clinical trial of treatment with MGN1703 (lefitolimod), an agonist of Toll-like receptor 9 (TLR9), as a potential strategy toward achieving a “functional cure” for human immunodeficiency virus (HIV) infection, defined as prolonged control of viremia without antiretroviral therapy (ART). After reading the report, two questions are likely to come to mind: What are Toll-like receptors, and how might their stimulation affect HIV that persists within the infected individual and leads to relapse despite prolonged, clinically effective ART? Toll-like receptors are a subfamily of pattern recognition receptors that recognize various unique components of prokaryotic, fungal, and viral pathogens and that stimulate key innate and adaptive immune responses to infection. They are named TLR because of their structural and functional similarity to the Drosophila transmembrane protein, Toll [1, 2]. TLR agonists, like MGN1703, mimic pathogen-associated molecular patterns (PAMPs) and can specifically enhance innate and adaptive responses. Unlike most of the TLR family, TLR3, TLR7, TLR8, and TLR9 are not located on the cell surface but rather on endosomal membranes—permitting the sensing of nucleic acid from intracellular pathogens. TLR3 is expressed primarily within dendritic cells (DCs) and senses retroviral double-stranded RNA (dsRNA), leading to the activation of interferon regulatory factor (IRF3), independent of the signaling adapter MyD88 [3, 4]. TLR7 and TLR8 sense single-stranded RNA and signal through the adapter protein MyD88 to activate interferon regulatory factors IRF5 and IRF7, leading to the activation of NF-κB and production of type I interferons (IFNs). TLR7 is expressed exclusively within plasmacytoid dendritic cells (pDCs) and B cells, whereas TLR8 is expressed within myeloid DCs [5–8]. TLR9, the target of MGN1703, is similar to the other intracellular TLRs but recognizes CpG-rich hypomethylated DNA motifs and signals through MyD88dependent mechanisms to activate IRF7 in pDCs [9–11]. Although binding of PAMPs to intracellular TLR triggers a variety of signaling mechanisms, they all converge on the transcription and production of type I IFNs from antigen-presenting cells, which have a critical role in protective immunity [12, 13]. Clinical applications of TLR agonists are common; they are used as antitumor agents for various types of cancer and as vaccine adjuvants. Bacterial BCG is a US Food and Drug Administration (FDA)–approved TLR1–2 agonist. Monophosphoryl lipid A, a TLR4 agonist, is an effective and nontoxic adjuvant vaccine adjuvant [14–16], as is polyinosinic:polycytidylic acid, a TLR3 agonist [17, 18]. The imidazoquinolinamines resiquimod and imiquimod are TLR7/8 agonists, which induce innate and adaptive immune responses, and imiquimod is currently FDA approved as a topical treatment for genital warts and superficial basal cell carcinoma [19–23]. Why, then, is TLR agonism being pursued as a means of eliminating or controlling HIV persistence? As broad stimulants of innate and adaptive immune responses, TLR agonism may affect HIV reservoirs through the widely pursued “kick and kill” approach to HIV cure [24]. This “kick and kill” approach aims to eliminate HIV-infected cells in 2 ways: (1) by reversing HIV latency, a major mechanism whereby HIV remains invisible to the immune system, and (2) by killing the newly exposed, HIV-infected cells through either direct viral protein–induced cytopathic effect or through immune-mediated mechanisms such as major histocompatibility complex (MHC) class I–restricted HIV-specific cytotoxic CD8+ T cells, cytotoxic natural killer (NK) cells, or antibody-dependent cytotoxic functions. Regarding the “kick” component of “kick and kill,” the latency reversing E D I T O R I A L C O M M E N T A R Y