title: Differential Control of BST2 Restriction and Plasmacytoid Dendritic Cell Antiviral Response by Antagonists Encoded by HIV-1 Group M and O Strains.
abstract: BST2/tetherin is a type I interferon (IFN-I)-stimulated host factor that restricts the release of HIV-1 by entrapping budding virions at the cell surface. This membrane-associated protein can also engage and activate the plasmacytoid dendritic cell (pDC)-specific immunoglobulin-like transcript 7 (ILT7) inhibitory receptor to downregulate the IFN-I response by pDCs. Pandemic HIV-1 group M uses Vpu (M-Vpu) to counteract the two BST2 isoforms (long and short) that are expressed in human cells. M-Vpu efficiently downregulates surface long BST2, while it displaces short BST2 molecules away from viral assembly sites. We recently found that this attribute is used by M-Vpu to activate the BST2/ILT7-dependent negative-feedback pathway and to suppress pDC IFN-I responses during sensing of infected cells. However, whether this property is conserved in endemic HIV-1 group O, which has evolved Nef (O-Nef) to counteract specifically the long BST2 isoform, remains unknown. In the present study, we validated that O-Nefs have the capacity to downregulate surface BST2 and enhance HIV-1 particle release although less efficiently than M-Vpu. In contrast to M-Vpu, O-Nef did not efficiently enhance viral spread in T cell culture or displace short BST2 from viral assembly sites to prevent its occlusion by tethered HIV-1 particles. Consequently, O-Nef impairs the ability of BST2 to activate negative ILT7 signaling to suppress the IFN-I response by pDC-containing peripheral blood mononuclear cells (PBMCs) during sensing of infected cells. These distinctive features of BST2 counteraction by O-Nefs may in part explain the limited spread of HIV-1 group O in the human population.
  
  
  OBJECTIVE
  The geographical distributions and prevalences of different HIV-1 groups show large variations. Understanding drivers of distinctive viral spread may aid in the development of therapeutic strategies for controlling the spread of HIV-1 pandemic strains. The differential spread of HIV-1 groups appears to be linked to their capacities to antagonize the long and short isoforms of the BST2 restriction factor. We found that the endemic HIV-1 group O-encoded BST2 antagonist Nef is unable to counteract the restriction mediated by short BST2, a condition that impairs its ability to activate ILT7 and suppress pDC antiviral responses. This is in contrast to the pandemic HIV-1 group M-specified BST2 countermeasure Vpu, which displays a diverse array of mechanisms to counteract short and long BST2 isoforms, an attribute that allows the effective control of pDC antiviral responses. These findings may help explain the limited spread of HIV-1 group O as well as the continued predominance of HIV-1 group M throughout the world.
authors: Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Quebec, Canada.
authors: Mariana G
authors: MG
authors: Bego
authors: Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Quebec, Canada.
authors: Lijun
authors: L
authors: Cong
authors: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors: Katharina
authors: K
authors: Mack
authors: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors: Frank
authors: F
authors: Kirchhoff
authors: Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Quebec, Canada eric.cohen@ircm.qc.ca.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.
authors: Éric A
authors: ÉA
authors: Cohen
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D000998:Antiviral Agents / Q000378:metabolism; D002460:Cell Line; D003713:Dendritic Cells / Q000378:metabolism* / Q000821:virology; D058851:GPI-Linked Proteins / Q000378:metabolism; D057809:HEK293 Cells; D015658:HIV Infections / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007372:Interferons / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D011971:Receptors, Immunologic / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D000998:Antiviral Agents; D058851:GPI-Linked Proteins; D007372:Interferons; D011971:Receptors, Immunologic; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C488262:LILRA4 protein, human