PDCs contribute to HIV persistence through depleting stem-like CD8 memory T cells

Abstract

Abstract Plasmacytoid dendritic cells (pDCs) rapidly produce type I interferons (IFN-I) to suppress HIV-1 replication during acute infection. However, persistent activation of pDCs during chronic HIV-1 infection contributes to HIV-1 diseases. The combination antiretroviral therapy (cART) effectively suppresses HIV-1 replication and extends the life span of HIV-infected individuals. However, the persistence of aberrant inflammation and HIV-1 reservoir cells in patients under cART leads to elevated inflammatory diseases and life-long HIV-1 persistence. We report here that pDC-depletion during suppressive cART in humanized mice resolved HIV-associated inflammatory diseases, reversed T cell immune hyper-activation and exhaustion, rescued anti-HIV T cell response. Importantly, pDC-depletion under cART reduced HIV-1 reservoirs in lymphoid tissues, associating with an increase of stem-like CD8 memory T cells (Tslc) in vivo. In vitro culture system, we confirmed that anti-HIV T cell response could also be enhanced by depleting pDC, accompanied with an increase of Tslc number. We conclude that pathogenic pDCs dysregulated anti-HIV T cell response and contributed to viral reservoir persistence via induction of persistent inflammation, immune activation and a consequent exhaustion/depletion of anti-HIV T cells. Depletion of pDCs rescued Tslc, correlated with HIV control in vivo. Targeting pDC may provide a novel strategy for treating HIV/cART-associated inflammatory diseases, controlling HIV-1 reservoirs during cART, approaching a functional cure for HIV infection.