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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Intravaginal
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Animals
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Aptamers, Nucleotide / administration & dosage
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Aptamers, Nucleotide / therapeutic use*
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Base Sequence
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CD4 Antigens / genetics
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CD4 Antigens / metabolism*
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CD4-Positive T-Lymphocytes / drug effects*
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CD4-Positive T-Lymphocytes / immunology
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Cell Polarity
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Cervix Uteri / drug effects*
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Cervix Uteri / virology
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Drug Evaluation, Preclinical
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Female
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Gene Expression Regulation / drug effects
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Gene Knockdown Techniques
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Genes, gag*
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Genes, vif*
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HIV Infections / prevention & control*
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HIV Infections / transmission
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Humans
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Macrophages / drug effects*
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Molecular Sequence Data
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Organ Culture Techniques
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / therapeutic use*
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Receptors, CCR5 / genetics*
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Species Specificity
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Transplantation Chimera / immunology
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Transplantation Chimera / virology*
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Vagina / drug effects*
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Vagina / virology
Substances
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Aptamers, Nucleotide
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CD4 Antigens
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RNA, Small Interfering
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Receptors, CCR5