title: Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras.
abstract: The continued spread of the HIV epidemic underscores the need to interrupt transmission. One attractive strategy is a topical vaginal microbicide. Sexual transmission of herpes simplex virus type 2 (HSV-2) in mice can be inhibited by intravaginal siRNA application. To overcome the challenges of knocking down gene expression in immune cells susceptible to HIV infection, we used chimeric RNAs composed of an aptamer fused to an siRNA for targeted gene knockdown in cells bearing an aptamer-binding receptor. Here, we showed that CD4 aptamer-siRNA chimeras (CD4-AsiCs) specifically suppress gene expression in CD4⁺ T cells and macrophages in vitro, in polarized cervicovaginal tissue explants, and in the female genital tract of humanized mice. CD4-AsiCs do not activate lymphocytes or stimulate innate immunity. CD4-AsiCs that knock down HIV genes and/or CCR5 inhibited HIV infection in vitro and in tissue explants. When applied intravaginally to humanized mice, CD4-AsiCs protected against HIV vaginal transmission. Thus, CD4-AsiCs could be used as the active ingredient of a microbicide to prevent HIV sexual transmission.
authors.affiliation: Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lee Adam
authors.initials: LA
authors.lastname: Wheeler
authors.forename: Radiana
authors.initials: R
authors.lastname: Trifonova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vrbanac
authors.forename: Emre
authors.initials: E
authors.lastname: Basar
authors.forename: Shannon
authors.initials: S
authors.lastname: McKernan
authors.forename: Zhan
authors.initials: Z
authors.lastname: Xu
authors.forename: Edward
authors.initials: E
authors.lastname: Seung
authors.forename: Maud
authors.initials: M
authors.lastname: Deruaz
authors.forename: Tim
authors.initials: T
authors.lastname: Dudek
authors.forename: Jon Ivar
authors.initials: JI
authors.lastname: Einarsson
authors.forename: Linda
authors.initials: L
authors.lastname: Yang
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tager
authors.forename: Derek M
authors.initials: DM
authors.lastname: Dykxhoorn
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000627:therapeutic use*; D001483:Base Sequence; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016764:Cell Polarity; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002584:Cervix Uteri / Q000187:drug effects* / Q000821:virology; D004353:Drug Evaluation, Preclinical; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D015750:Genes, gag; D016341:Genes, vif; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000627:therapeutic use*; D019713:Receptors, CCR5 / Q000235:genetics*; D013045:Species Specificity; D018183:Transplantation Chimera / Q000276:immunology / Q000821:virology*; D014621:Vagina / Q000187:drug effects* / Q000821:virology
chemical_list: D052157:Aptamers, Nucleotide; D015704:CD4 Antigens; D034741:RNA, Small Interfering; D019713:Receptors, CCR5