title: HIV-1 Env and Nef Cooperatively Contribute to Plasmacytoid Dendritic Cell Activation via CD4-Dependent Mechanisms.
abstract: Plasmacytoid dendritic cells (pDCs) are the major source of type I IFN (IFN-I) in response to human immunodeficiency virus type 1 (HIV-1) infection. pDCs are rapidly activated during HIV-1 infection and are implicated in reducing the early viral load, as well as contributing to HIV-1-induced pathogenesis. However, most cell-free HIV-1 isolates are inefficient in activating human pDCs, and the mechanisms of HIV-1 recognition by pDCs and pDC activation are not clearly defined. In this study, we report that two genetically similar HIV-1 variants (R3A and R3B) isolated from a rapid progressor differentially activated pDCs to produce alpha interferon (IFN-α). The highly pathogenic R3A efficiently activated pDCs to induce robust IFN-α production, while the less pathogenic R3B did not. The viral determinant for efficient pDC activation was mapped to the V1V2 region of R3A Env, which also correlated with enhanced CD4 binding activity. Furthermore, we showed that the Nef protein was also required for the activation of pDCs by R3A. Analysis of a panel of R3A Nef functional mutants demonstrated that Nef domains involved in CD4 downregulation were necessary for R3A to activate pDCs. Our data indicate that R3A-induced pDC activation depends on (i) the high affinity of R3A Env for binding the CD4 receptor and (ii) Nef activity, which is involved in CD4 downregulation. Our findings provide new insights into the mechanism by which HIV-1 induces IFN-α in pDCs, which contributes to pathogenesis.
  
  
  OBJECTIVE
  Plasmacytoid dendritic cells (pDCs) are the major type I interferon (IFN-I)-producing cells, and IFN-I actually contributes to pathogenesis during chronic viral infections. How HIV-1 activates pDCs and the roles of pDCs/IFN-I in HIV-1 pathogenesis remain unclear. We report here that the highly pathogenic HIV R3A efficiently activated pDCs to induce IFN-α production, while most HIV-1 isolates are inefficient in activating pDCs. We have discovered that R3A-induced pDC activation depends on (i) the high affinity of R3A Env for binding the CD4 receptor and (ii) Nef activity, which is involved in CD4 downregulation. Our findings thus provide new insights into the mechanism by which HIV-1 induces IFN-α in pDCs and contributes to HIV-1 pathogenesis. These novel findings will be of great interest to those working on the roles of IFN and pDCs in HIV-1 pathogenesis in general and on the interaction of HIV-1 with pDCs in particular.
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA lishan_su@med.unc.edu reszka@email.unc.edu.
authors.forename: Natalia J
authors.initials: NJ
authors.lastname: Reszka-Blanco
authors.affiliation: Department of Biology, College of Arts and Science, North Carolina Central University, Durham, North Carolina, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Sivaraman
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Liguo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA lishan_su@med.unc.edu reszka@email.unc.edu.
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
mesh_terms: D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D016898:Interferon-alpha; D054299:env Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1