Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras
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 knoc...
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| Veröffentlicht in: | The Journal of clinical investigation 2011-06, Vol.121 (6), p.2401-2412 |
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| creator | Wheeler, Lee Adam Trifonova, Radiana Vrbanac, Vladimir Basar, Emre McKernan, Shannon Xu, Zhan Seung, Edward Deruaz, Maud Dudek, Tim Einarsson, Jon Ivar Yang, Linda Allen, Todd M Luster, Andrew D Tager, Andrew M Dykxhoorn, Derek M Lieberman, Judy |
| description | 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. |
| doi_str_mv | 10.1172/JCI45876 |
| format | Article |
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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.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI45876</identifier><identifier>PMID: 21576818</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Administration, Intravaginal ; Animals ; Anti-infective agents ; Aptamers, Nucleotide - administration & dosage ; Aptamers, Nucleotide - therapeutic use ; Base Sequence ; Biomedical research ; CD4 Antigens - genetics ; CD4 Antigens - metabolism ; CD4-Positive T-Lymphocytes - drug effects ; CD4-Positive T-Lymphocytes - immunology ; Cell Polarity ; Cells, Cultured - drug effects ; Cells, Cultured - metabolism ; Cervix Uteri - drug effects ; Cervix Uteri - virology ; Disease transmission ; Drug Evaluation, Preclinical ; Female ; Flow cytometry ; Gene expression ; Gene Expression Regulation - drug effects ; Gene Knockdown Techniques ; Genes ; Genes, gag ; Genes, vif ; Health aspects ; Herpes viruses ; HIV ; HIV (Viruses) ; HIV Infections - prevention & control ; HIV Infections - transmission ; Human immunodeficiency virus ; Humans ; Infection ; Infections ; Lymphocytes ; Macrophages - drug effects ; Macrophages - immunology ; Macrophages - metabolism ; Medical equipment and supplies industry ; Medical test kit industry ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Molecular Sequence Data ; Organ Culture Techniques ; Prostate ; Receptors, CCR5 - genetics ; RNA, Small Interfering - administration & dosage ; RNA, Small Interfering - therapeutic use ; Species Specificity ; T cells ; Transplantation Chimera - immunology ; Transplantation Chimera - virology ; Vagina ; Vagina - drug effects ; Vagina - virology</subject><ispartof>The Journal of clinical investigation, 2011-06, Vol.121 (6), p.2401-2412</ispartof><rights>COPYRIGHT 2011 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Jun 2011</rights><rights>Copyright © 2011, American Society for Clinical Investigation 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c668t-5531dc38c8c07549b056c67874127c7d19b4e54baa07e5812e5683b5f2dee9bc3</citedby><cites>FETCH-LOGICAL-c668t-5531dc38c8c07549b056c67874127c7d19b4e54baa07e5812e5683b5f2dee9bc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104760/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104760/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21576818$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wheeler, Lee Adam</creatorcontrib><creatorcontrib>Trifonova, Radiana</creatorcontrib><creatorcontrib>Vrbanac, Vladimir</creatorcontrib><creatorcontrib>Basar, Emre</creatorcontrib><creatorcontrib>McKernan, Shannon</creatorcontrib><creatorcontrib>Xu, Zhan</creatorcontrib><creatorcontrib>Seung, Edward</creatorcontrib><creatorcontrib>Deruaz, Maud</creatorcontrib><creatorcontrib>Dudek, Tim</creatorcontrib><creatorcontrib>Einarsson, Jon Ivar</creatorcontrib><creatorcontrib>Yang, Linda</creatorcontrib><creatorcontrib>Allen, Todd M</creatorcontrib><creatorcontrib>Luster, Andrew D</creatorcontrib><creatorcontrib>Tager, Andrew M</creatorcontrib><creatorcontrib>Dykxhoorn, Derek M</creatorcontrib><creatorcontrib>Lieberman, Judy</creatorcontrib><title>Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>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.</description><subject>Administration, Intravaginal</subject><subject>Animals</subject><subject>Anti-infective agents</subject><subject>Aptamers, Nucleotide - administration & dosage</subject><subject>Aptamers, Nucleotide - therapeutic use</subject><subject>Base Sequence</subject><subject>Biomedical research</subject><subject>CD4 Antigens - genetics</subject><subject>CD4 Antigens - metabolism</subject><subject>CD4-Positive T-Lymphocytes - drug effects</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>Cell Polarity</subject><subject>Cells, Cultured - drug effects</subject><subject>Cells, Cultured - metabolism</subject><subject>Cervix Uteri - drug effects</subject><subject>Cervix Uteri - virology</subject><subject>Disease transmission</subject><subject>Drug Evaluation, Preclinical</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Gene Knockdown Techniques</subject><subject>Genes</subject><subject>Genes, gag</subject><subject>Genes, vif</subject><subject>Health aspects</subject><subject>Herpes viruses</subject><subject>HIV</subject><subject>HIV (Viruses)</subject><subject>HIV Infections - prevention & control</subject><subject>HIV Infections - transmission</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Infection</subject><subject>Infections</subject><subject>Lymphocytes</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Medical equipment and supplies industry</subject><subject>Medical test kit industry</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Molecular Sequence Data</subject><subject>Organ 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clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2011-06-01</date><risdate>2011</risdate><volume>121</volume><issue>6</issue><spage>2401</spage><epage>2412</epage><pages>2401-2412</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><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.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>21576818</pmid><doi>10.1172/JCI45876</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-9738 |
| ispartof | The Journal of clinical investigation, 2011-06, Vol.121 (6), p.2401-2412 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3104760 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Administration, Intravaginal Animals Anti-infective agents Aptamers, Nucleotide - administration & dosage Aptamers, Nucleotide - therapeutic use Base Sequence Biomedical research CD4 Antigens - genetics CD4 Antigens - metabolism CD4-Positive T-Lymphocytes - drug effects CD4-Positive T-Lymphocytes - immunology Cell Polarity Cells, Cultured - drug effects Cells, Cultured - metabolism Cervix Uteri - drug effects Cervix Uteri - virology Disease transmission Drug Evaluation, Preclinical Female Flow cytometry Gene expression Gene Expression Regulation - drug effects Gene Knockdown Techniques Genes Genes, gag Genes, vif Health aspects Herpes viruses HIV HIV (Viruses) HIV Infections - prevention & control HIV Infections - transmission Human immunodeficiency virus Humans Infection Infections Lymphocytes Macrophages - drug effects Macrophages - immunology Macrophages - metabolism Medical equipment and supplies industry Medical test kit industry Mice Mice, Inbred NOD Mice, SCID Molecular Sequence Data Organ Culture Techniques Prostate Receptors, CCR5 - genetics RNA, Small Interfering - administration & dosage RNA, Small Interfering - therapeutic use Species Specificity T cells Transplantation Chimera - immunology Transplantation Chimera - virology Vagina Vagina - drug effects Vagina - virology |
| title | Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T10%3A12%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Inhibition%20of%20HIV%20transmission%20in%20human%20cervicovaginal%20explants%20and%20humanized%20mice%20using%20CD4%20aptamer-siRNA%20chimeras&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Wheeler,%20Lee%20Adam&rft.date=2011-06-01&rft.volume=121&rft.issue=6&rft.spage=2401&rft.epage=2412&rft.pages=2401-2412&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI45876&rft_dat=%3Cgale_pubme%3EA348997217%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=872088414&rft_id=info:pmid/21576818&rft_galeid=A348997217&rfr_iscdi=true |