Most of the antiviral agents that are either available, such as acyclovir and famciclovir, or in development, inhibit pathways that are involved in viral replication or assembly. By contrast, the antiviral drug imiquimod, which is an imidazoquinoline amine, is an immune-response modifier that activates immune function. In the February issue of Nature Immunology, Shizuo Akira and colleagues show that imidazoquinolines activate immune cells by means of the Toll-like receptor 7 (TLR7) signalling pathway, which leads to the induction of interferon-α and other inflammatory cytokines.
Toll-like receptors (TLRs) are named from the Toll gene of Drosophila melanogaster. As well as being involved in development, TLRs are also a vital component in the fly's immune response to infections. So far, ten mammalian TLRs have been reported, each essential for recognition of specific bacterial, viral and fungal components. They associate with a protein, MYD88, which acts as an adaptor that leads to activation of both the transcription factor NF-κB and the JNK MAP kinase. So, TLRs link microbial products to transcription, and the immune response is set in motion. Akira and colleagues showed in vivo that imiquimod and resiquimod, a related compound, activate immune cells in a TLR7- and MYD88-dependent manner. Furthermore, neither Tlr7- nor Myd88-deficient mice showed inflammatory cytokine production by any immune cells, or maturation of immune-initiator dendritic cells in response to imidazoquinolines. Mature dendritic cells are crucial for inducing immune responses by displaying small amounts of foreign components to effector T cells.
The more potent resiquimod is undergoing Phase III clinical trials at present for genital herpes. The continuing trials indicate that resiquimod increases the time between genital herpes outbreaks, and could produce a long-lasting suppressive effect without the need for daily therapy. Through its novel approach of activating the immune system as if it is a vaccine, some clinical investigators believe resiquimod might reduce viral transmission and, with several courses of therapy, place the disease into clinical remission.
Interferon-α, which is produced by dendritic cells, is the body's natural defence against many viruses. In addition, certain subsets of dendritic cells express TLR7 and TLR9 exclusively out of the ten known TLR family members. The essential role of TLR7 in the response to these viral agents provides compelling evidence for its general involvement in antiviral host defence. This mechanistic understanding that imidazoquinolines stimulate the immune system through TLR7 is welcome news for the future design of antivirals based on TLR7 ligands. This work raises new questions about whether TLR7 interacts directly with viruses on infection. Furthermore, because each Toll receptor recognizes different microbial components, these receptors might be useful as specific antibacterial and antifungal targets.
ORIGINAL RESEARCH PAPER
Hemmi, H. et al. Antiviral low molecular weight compounds activate immune cells via TLR7–MyD88-dependent signalling pathway. Nature Immunol. 2002 Jan 22 (DOI 10.1038/ni758)
Akira, S. et al. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675–680 (2001)
Rights and permissions
About this article
Cite this article
Brazil, M. Antivirals pay the Toll. Nat Rev Drug Discov 1, 96 (2002). https://doi.org/10.1038/nrd733