title: Plasmacytoid dendritic cells suppress HIV-1 replication but contribute to HIV-1 induced immunopathogenesis in humanized mice.
abstract: 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.
authors: Key Lab of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Guangming
authors: G
authors: Li
authors: Key Lab of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors: Menglan
authors: M
authors: Cheng
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Jun-Ichi
authors: J
authors: Nunoya
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Liang
authors: L
authors: Cheng
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Haitao
authors: H
authors: Guo
authors: Key Lab of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors: Haisheng
authors: H
authors: Yu
authors: Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, Texas, United States of America.
authors: Yong-Jun
authors: YJ
authors: Liu
authors: Key Lab of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Lishan
authors: L
authors: Su
authors: Key Lab of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors: Liguo
authors: L
authors: Zhang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015153:Blotting, Western; D002478:Cells, Cultured; D004261:DNA Replication; D003713:Dendritic Cells / Q000276:immunology*; D005333:Fetus / Q000166:cytology / Q000276:immunology / Q000821:virology; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D007124:Immunoenzyme Techniques; D007372:Interferons; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014766:Viremia / Q000276:immunology*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D007372:Interferons