Modification of immune activation in HIV-1-infected humanized mouse model using TLR7/9 antagonists (113.19)

Abstract Background: T cell immune activation is a strong predictor of HIV-1 disease progression, and IFNα production following TLR7 stimulation has been associated with elevated CD8+ T cell activation. We hypothesize that modulation of TLR7 stimulation could be used to manipulate IFNα production and subsequently reduce HIV-1-associated immune activation. Methods: Humanized BLT mice were generated by transplanting irradiated NOD/SCID/IL2Rγc-/- mice with human fetal thymus, liver tissue and human hematopoietic stem cells. After immune reconstitution, human DC, monocyte and T cell populations were detectable in the mice, and in vitro TLR responsiveness of DCs and monocytes reflected those observed in human PBMCs. Humanized mice were infected with HIV-1 and then treated with a TLR7/9 antagonist. The T cell activation markers were examined at each stage by flow cytometry. Results: BLT mice-derived human pDC responses to TLR7 stimulation were significantly blocked by in vitro treatment with the TLR7/9 antagonist (P<0.05). HIV-1 infection of BLT mice led to increased expression of immune activation marker CD38 on human T cells in vivo, and treatment of infected mice with the TLR7/9 antagonist led to a significant reduction in CD38 expression. Conclusion: Treatment of HIV-1-infected humanized BLT mice with TLR7/9 antagonist resulted in significant reduction of HIV-1-associated immune activation, indicating an important role of the TLR7/9 pathway in mediating immune activation in HIV-1.