TLR-mediated immune activation in HIV

In this issue of Blood, Baenziger and colleagues demonstrate that chronic triggering of TLR7 in mice using soluble synthetic or HIV-1–derived TLR7 ligands leads to immune activation and disruption of lymphoid architecture similar to those observed in chronic HIV-1 infection in humans.

The link between immune activation and HIV-1 disease progression has now been well established. However, the mechanisms through which HIV-1 induces immune activation are still debated. Recently, the Toll-like receptor (TLR) pathway has been implicated in contributing to the persistent immune activation observed in chronically HIV-1–infected individuals. Studies consistent with the “leaky gut” model have shown that the depletion of CD4⁺ T cells in the gastrointestinal tract of HIV-1–positive individuals allows for components of bacterial pathogens, including lipopolysaccharide, to enter the blood stream and increase T-cell activation via stimulation of TLR4.¹  Furthermore, it has been demonstrated that HIV-1 encodes for multiple TLR7/8 ligands that can mediate direct activation of the immune system in vitro.^2,3  In this issue of Blood, Baenziger et al now provide further evidence for a role of chronic TLR stimulation in HIV-1 pathogenesis. They use a murine model to show that chronic activation of TLR7 can directly lead to immune activation as well as an array of immune dysfunction similar to those observed in human HIV-1 chronic infection. These findings are consistent with previously published studies using TLR9 ligands that also induced lymphoid follicle destruction and immunosuppression in mice following chronic administration.⁴ 

The studies of Baenziger et al in the murine model are of interest, but significant differences between humans and mice, including the inability of mouse TLR8 to recognize the TLR ligands used and deviations in the cytokine profile in response to TLR7 stimulation, represent important confounding factors.⁵  Interestingly, recent data from the nonhuman primate model of HIV-1 infection provide additional support for a role of the TLR7 pathway in HIV-1 pathogenesis. Simian immunodeficiency virus (SIV) infection in rhesus macaques induces strong immune activation and pathogenesis while SIV infection of sooty mangabeys, the natural host of SIV, does not cause disease and results in significantly less immune activation, particularly during chronic infection. A recent publication by Mandl et al showed that stimulation with SIV or TLR7 ligands induced much stronger IFNα production by plasmacytoid dendritic cells (pDCs) derived from rhesus macaques compared with pDCs derived from sooty mangabeys. In addition, the stimulation implicated genetic differences in IRF-7 between these 2 species as a potential explanation of the observed differences in pDC responses to TLR7 ligands.⁶  Although the presence of TLR7-mediated immune activation in the primate model of pathogenic SIV infection is consistent with the murine study, Baenziger et al did not observe elevated IFNα production after prolonged stimulation of TLR7 in the mouse, and the immune dysfunction was only partially dampened in both IFNAR^−/− and IRF7^−/− mice. It is unclear whether these discrepancies are due to differences between the species. However, the observed abrogation of immune dysfunction induced by TLR7 ligands in MyD88^−/− and TLR7^−/− knock-out mice strongly suggests the involvement of TLR7 and its downstream pathways.

Taken together, these recent studies are consistent with a model in which chronic stimulation of the innate immune system by TLR ligands, either encoded by HIV-1 or found in the circulation after microbial translocation from the gut, result in the chronic production of proinflammatory cytokines driving generalized immune activation and disease progression in HIV-1–infected individuals. Similar to hepatitis C virus infection, another chronic persistent viral infection in which genetic polymorphisms in TLR7 have been associated with differences in liver fibrosis,⁷  recent studies have associated polymorphisms in TLRs with differential HIV-1 disease outcome,⁸  further supporting this model. At this point, studies in humans are needed to examine this model and its significance for HIV-1 pathogenesis. The recent developments of TLR antagonists that can block TLR signaling make such studies possible. The reduction of chronic immune activation via TLR stimulation might represent an attractive potential target to reduce immunopathology in chronic HIV-1 infection.