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Review
. 2023 Jan 5;12(1):92.
doi: 10.3390/pathogens12010092.

Role of TLRs in HIV-1 Infection and Potential of TLR Agonists in HIV-1 Vaccine Development and Treatment Strategies

Marija Rozman  1 , Snjezana Zidovec-Lepej  1 , Karlo Jambrosic  2 , Maja Babić  3 , Irena Drmić Hofman  4   5
Affiliations
Review

Role of TLRs in HIV-1 Infection and Potential of TLR Agonists in HIV-1 Vaccine Development and Treatment Strategies

Marija Rozman et al. Pathogens. .

Abstract

Toll-like receptors (TLRs), as a family of pattern recognition receptors, play an important role in the recognition of HIV-1 molecular structures by various cells of the innate immune system, but also provide a functional association with subsequent mechanisms of adaptive immunity. TLR7 and TLR8 play a particularly important role in the innate immune response to RNA viruses due to their ability to recognise GU-rich single-stranded RNA molecules and subsequently activate intracellular signalling pathways resulting in expression of genes coding for various biological response modifiers (interferons, proinflammatory cytokines, chemokines). The aim of this review is to summarise the most recent knowledge on the role of TLRs in the innate immune response to HIV-1 and the role of TLR gene polymorphisms in the biology and in the clinical aspects of HIV infections. In addition, the role of TLR agonists as latency reversing agents in research to treat HIV infections and as immunomodulators in HIV vaccine research will be discussed.

Keywords: HIV-1; TLR agonists; Toll-like receptors (TLRs); innate immunity; latency reversing agents (LRAs).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of HIV-1.
Figure 2
Figure 2
Mechanism of HIV-1 infection. (1) Binding, fusion, and entry of the HIV-1 virion into the host cell. (2) Uncoating of viral single-stranded (ssRNA) and reverse transcription into DNA. (3) Integration of synthesised double-stranded (dsDNA) into the host genome (provirus). (4) Protein synthesis and assembly. (5) Virion assembly. (6) Release of new HIV-1 virion. (7) Maturation.
Figure 3
Figure 3
Induction of signalling TLRs. (a) TLR5 is expressed on the cell membrane; after binding its ligand flagellin, dimerization of the two TLR5 receptors occurs. Dimerization of the TIR-domains causes the recruitment of Myd88 and, along with IRAKs, formation of the myddosome. This initiates a signalling pathway that activates NF-κB and leads to the synthesis of proinflammatory cytokines. Other TLRs expressed on the cell membrane including TLR5, TLR1, TLR2, TLR4, TLR6, and TLR10 initiate the Myd88 signalling pathway. (b) TLR3 is the only receptor that strictly uses the TRIF signalling pathway. TLR3 is positioned on the endosomal membrane and is activated by binding of its ligand, dsRNA. Followed by ligand binding, dimerization of TLR3 occurs. TLR3 uses the TRIF signalling pathway where TRIF recruits IKKε and TBK1, leading to activation of NF-κB, IRAK3, and AP-1 and, consequently, synthesis of proinflammatory cytokines and type I interferons (type I IFNs). Other TLRs on the endosomal membrane are TLR7, TLR8, and TLR9. However, they use the Myd88 signalling pathway while TLR3 is the only receptor that strictly uses the TRIF-signalling pathway. TLR4 can use both the Myd88 signalling pathway and TRIF signalling pathway.
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