title: Constitutively Active MAVS Inhibits HIV-1 Replication via Type I Interferon Secretion and Induction of HIV-1 Restriction Factors.
abstract: Type I interferon is known to inhibit HIV-1 replication through the induction of interferon stimulated genes (ISG), including a number of HIV-1 restriction factors. To better understand interferon-mediated HIV-1 restriction, we constructed a constitutively active form of the RIG-I adapter protein MAVS. Constitutive MAVS was generated by fusion of full length MAVS to a truncated form of the Epstein Barr virus protein LMP1 (ΔLMP1). Supernatant from ΔLMP1-MAVS-transfected 293T cells contained high levels of type I interferons and inhibited HIV replication in both TZM-bl and primary human CD4+ T cells. Supernatant from ΔLMP1-MAVS-transfected 293T cells also inhibited replication of VSV-G pseudotyped single cycle SIV in TZM-bl cells, suggesting restriction was post-entry and common to both HIV and SIV. Gene array analysis of ΔLMP1-MAVS-transfected 293T cells and trans-activated CD4+ T cells showed significant upregulation of ISG, including previously characterized HIV restriction factors Viperin, Tetherin, MxB, and ISG56. Interferon blockade studies implicated interferon-beta in this response. In addition to direct viral inhibition, ΔLMP1-MAVS markedly enhanced secretion of IFN-β and IL-12p70 by dendritic cells and the activation and maturation of dendritic cells. Based on this immunostimulatory activity, an adenoviral vector (Ad5) expressing ΔLMP1-MAVS was tested as a molecular adjuvant in an HIV vaccine mouse model. Ad5-Gag antigen combined with Ad5-ΔLMP1-MAVS enhanced control of vaccinia-gag replication in a mouse challenge model, with 4/5 animals showing undetectable virus following challenge. Overall, ΔLMP1-MAVS is a promising reagent to inhibit HIV-1 replication in infected tissues and enhance vaccine-mediated immune responses, while avoiding toxicity associated with systemic type I interferon administration.
authors: Department of Microbiology and Immunology, Miami Center for AIDS Research and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors: Sachin
authors: S
authors: Gupta
authors: Department of Microbiology and Immunology, Miami Center for AIDS Research and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors: James M
authors: JM
authors: Termini
authors: Division of Bioinformatics, Biostatistics and Bioinformatics Core, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors: Biju
authors: B
authors: Issac
authors: Department of Microbiology and Immunology, Miami Center for AIDS Research and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors: Elizabeth
authors: E
authors: Guirado
authors: Department of Microbiology and Immunology, Miami Center for AIDS Research and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors: Geoffrey W
authors: GW
authors: Stone
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015703:Antigens, CD / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism* / Q000502:physiology; D064547:Myxovirus Resistance Proteins / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D000074010:Bone Marrow Stromal Antigen 2; D000090123:Viperin Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D058851:GPI-Linked Proteins; D016899:Interferon-beta; D064547:Myxovirus Resistance Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C484290:IFIT1 protein, human; C505371:MAVS protein, human; C579068:MX2 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein