Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice

The role of plasmacytoid dendritic cells (pdc) in human immunodeficiency virus type 1 (hiv-1) infection and pathogenesis remains unclear. hiv-1 infection in the humanized mouse model leads to persistent hiv-1 infection and immunopathogenesis,including type i interferons (ifn-i) induction,immune-activation and depletion of human leukocytes,including cd4 t cells. we developed a monoclonal antibody that specifically depletes human pdc in all lymphoid organs in humanized mice. when pdc were depleted prior to hiv-1 infection,the induction of ifn-i and interferon-stimulated genes (isgs) were abolished during acute hiv-1 infection with either a highly pathogenic ccr5/cxcr4-dual tropic hiv-1 or a standard ccr5-tropic hiv-1 isolate. consistent with the anti-viral role of ifn-i,hiv-1 replication was significantly up-regulated in pdc-depleted mice. interestingly,the cell death induced by the highly pathogenic hiv-1 isolate was severely reduced in pdc-depleted mice. during chronic hiv-1 infection,depletion of pdc also severely reduced the induction of ifn-i and isgs,associated with elevated hiv-1 replication. surprisingly,hiv-1 induced depletion of human immune cells including t cells in lymphoid organs,but not the blood,was reduced in spite of the increased viral replication. the increased cell number in lymphoid organs was associated with a reduced level of hiv-induced cell death in human leukocytes including cd4 t cells. we conclude that pdc play opposing roles in suppressing hiv-1 replication and in promoting hiv-1 induced immunopathogenesis. these findings suggest that pdc-depletion and ifn-i blockade will provide novel strategies for treating those hiv-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment. © 2014 li et al.