Jean-François Bolduc, Michel Ouellet, Laurent Hany, Michel J. Tremblay; Toll-Like Receptor 2 Ligation Enhances HIV-1 Replication in Activated CCR6+ CD4+ T Cells by Increasing Virus Entry and Establishing a More Permissive Environment to Infection. Journal of virology (2017) 91(4) : e01402-16
In this study, the authors investigated the effect of Toll-like receptor 2 (TLR2) ligation on the permissiveness of activated CD4+ T cells to HIV-1 infection by focusing their experiments on the relative susceptibility of cell subsets based on their expression of CCR6. Purified primary human CD4+ T cells were first subjected to a CD3/CD28 costimulation before treatment with the TLR2 agonist Pam3CSK4. Finally, cells were inoculated with R5-tropic HIV-1 particles that allowed them to study the effect of TLR2 triggering on virus production at both population and single-cell levels. They report that HIV-1 replication is augmented in CD3/CD28-costimulated CCR6+ CD4+ T cells upon engagement of the cell surface TLR2. Additional studies indicate that a higher virus entry and polymerization of the cortical actin are observed in this cell subset following TLR2 stimulation. A TLR2-mediated increase in the level of phosphorylated NF-κB p65 subunit was also detected in CD3/CD28-costimulated CCR6+ CD4+ T cells. The authors propose that, upon antigenic presentation, an engagement of TLR2 acts specifically on CCR6+ CD4+ T cells by promoting virus entry in an intracellular milieu more favorable for productive HIV-1 infection.
Following primary infection, HIV-1 induces an immunological and structural disruption of the gut mucosa, leading to bacterial translocation and release of microbial components in the bloodstream. These pathogen-derived constituents include several agonists of Toll-like receptors that may affect gut-homing CD4+ T cells, such as those expressing the chemokine receptor CCR6, which are highly permissive to HIV-1 infection. We demonstrate that TLR2 ligation in CD3/CD28-costimulated CCR6+ CD4+ T cells leads to enhanced virus production. The authors’ results highlight the potential impact of bacterial translocation on the overall permissiveness of CCR6+ CD4+ T cells to productive HIV-1 infection.
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Research funded by the CIHR.