title: TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice.
abstract: Despite their antiviral effect, the in vivo effect of interferons on HIV transmission is difficult to predict, because interferons also activate and recruit HIV-susceptible cells to sites of infection. HIV does not normally induce type I interferons in infected cells, but does if TREX1 is knocked down. Here, we investigated the effect of topical TREX1 knockdown and local interferon production on HIV transmission in human cervicovaginal explants and humanized mice. In explants in which TREX1 was knocked down, HIV induced interferons, which blocked infection. In humanized mice, even though TREX1 knockdown increased infiltrating immune cells, it delayed viral replication for 3-4 weeks. Similarly intravaginal application of type I interferons the day before HIV infection induced interferon responsive genes, reduced inflammation, and decreased viral replication. However, intravenous interferon enhanced inflammation and infection. Thus, in models of human sexual transmission, a localized interferon response inhibits HIV transmission but systemic interferons do not.
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lee Adam
authors.initials: LA
authors.lastname: Wheeler
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Radiana T
authors.initials: RT
authors.lastname: Trifonova
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02139, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vrbanac
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Natasha S
authors.initials: NS
authors.lastname: Barteneva
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Brooke
authors.initials: B
authors.lastname: Bollman
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Onofrey
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Mulik
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Ranjbar
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02139, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02139, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tager
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: judy.lieberman@childrens.harvard.edu.
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002584:Cervix Uteri / Q000473:pathology; D002678:Chimera; D005090:Exodeoxyribonucleases / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006678:HIV / Q000502:physiology; D015658:HIV Infections / Q000201:enzymology* / Q000473:pathology / Q000635:transmission / Q000821:virology*; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics; D014621:Vagina / Q000473:pathology; D014779:Virus Replication
chemical_list: D010750:Phosphoproteins; D034741:RNA, Small Interfering; D016899:Interferon-beta; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1