Plasmacytoid Dendritic Cells Impair Anti-HIV Immunity and HIV-1 Persistence During Antiretroviral Therapy Via IDO-Dependent Mechanisms

The persistence of aberrant inflammation and HIV-1 reservoir cells in patients under effective combination antiretroviral therapy (cART) leads to elevated inflammatory diseases and life-long HIV-1 persistence. Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFN-I) during acute and chronic HIV-1 infection. We report here that pDC-depletion during suppressive cART in humanized mice resolved HIV-associated inflammatory diseases, rescued anti-HIV T cells and reduced HIV-1 reservoirs in lymphoid and other tissues. Furthermore, we found that HIV-1 infection induced indoleamine 2,3-dioxygenase (IDO) expression in a pDC-dependent fashion in vivo. IDO inhibition similarly reversed HIV-1 immune pathogenesis, rescued anti-HIV T cells and reduced HIV reservoirs in cART-treated mice. We conclude that pathogenic pDCs contribute to HIV/cART-associated inflammatory diseases, impairment of anti-HIV T cells, and HIV-1 reservoir persistence via IDO induction during effective cART in vivo. Targeting the pDC-IDO axis will provide a novel strategy for treating HIV/cART-associated inflammatory diseases and for HIV-1 cure.