The Role of Toll-Like Receptors in Retroviral Infection

Abstract

Toll-like receptors (TLRs) are key pathogen sensing receptors that respond to diverse microbial ligands, and trigger both innate and adaptive immune responses to infection. Since their discovery, a growing body of evidence has pointed to an important role for TLRs in retroviral infection and pathogenesis. These data suggest that multiple TLRs contribute to the anti-retroviral response, and that TLR engagement by retroviruses can have complex and divergent outcomes for infection. Despite this progress, numerous questions remain about the role of TLRs in retroviral infection. In this review, I summarize existing evidence for TLR-retrovirus interactions and the functional roles these receptors play in immunity and pathogenesis, with particular focus on human immunodeficiency virus (HIV).

Keywords: Toll-Like Receptors (TLRs); human immunodeficiency virus (HIV); innate immunity; interferon; retrovirus.

Figure 1

Sensing of retroviral infection by Toll-like receptors (TLRs). Retroviruses can be detected by several TLRs, by both direct and indirect mechanisms. TLR2/6 and TLR10 sense HIV viral structural proteins Gag (p17, p24) and Envelope (gp41, gp120) at the plasma membrane, while TLR4 detects Env or Tat. TLR4 can also be engaged by virion-associated LPS or translocated bacteria from mucosa. Endosomal TLRs are activated by viral ssRNA (TLR7, TLR8), viral dsRNA (TLR3) or by dsDNA (TLR9), possibly of host origin.

Figure 2

Complex outcomes of retrovirus-TLR interactions. Engagement of TLRs by retroviral particles during infection can have complex and opposing effects on retroviral replication. Activation of a TLR by retroviral PAMPs in an infected cell, either at the plasma membrane, or at an endosomal membrane, triggers activation of NF-κB and IRF3, leading to increased expression of immune modulating cytokines and type 1 interferons (IFNs). NF-κB activation also directly promotes HIV transcription. Cytokines/IFNs can then promote DC maturation and shape T cell activation/polarization. Dendritic cells (DCs) can also directly sense HIV through TLR7 to promote maturation or IFN secretion. IFNs bind to the IFNAR1/2 complex to promote expression of interferon sensitive genes (ISGs) including retroviral restriction factors such as APOBEC3G, BST2 and SAMHD1. B cell intrinsic detection of retroviruses through TLR7 promotes virus-specific antibody responses.