An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection
Abstract
Herpes simplex virus 2 (HSV-2) infection causes significant morbidity and is an important cofactor for the transmission of HIV infection. A microbicide to prevent sexual transmission of HSV-2 would contribute substantially to controlling the spread of HIV and other infections. Because RNA interference (RNAi) provides effective antiviral defence in plants and other organisms, several studies have focused on harnessing RNAi to inhibit viral infection. Here we show that vaginal instillation of small interfering RNAs (siRNAs) targeting HSV-2 protects mice from lethal infection. siRNAs mixed with lipid are efficiently taken up by epithelial and lamina propria cells and silence gene expression in the mouse vagina and ectocervix for at least nine days. Intravaginal application of siRNAs targeting the HSV-2 UL27 and UL29 genes (which encode an envelope glycoprotein and a DNA binding protein, respectively) was well tolerated, did not induce interferon-responsive genes or cause inflammation, and protected mice when administered before and/or after lethal HSV-2 challenge. These results suggest that siRNAs are attractive candidates for the active component of a microbicide designed to prevent viral infection or transmission.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In a mouse model of lethal HSV-2 infection, intravaginal administration of oligofectamine-complexed siRNA targeting genes encoding viral envelope and DNA binding proteins resulted in improved survival compared with untreated controls.
“In a mouse model of lethal HSV-2 infection, intravaginal administration of oligofectamine-complexed small interfering RNA (siRNA) targeting genes encoding viral envelope and DNA binding proteins resulted in improved survival compared with untreated controls 27 .”
From Nanotechnology approaches for global infectious diseases (2021) · cites this paper as [27]
Cites
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1992) · Springer series in statistics · doi:10.1007/978-1-4612-4380-9_25 · Cited by 45,232 · see citing works
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1958) · Journal of the American Statistical Association · doi:10.1080/01621459.1958.10501452 · Cited by 39,158 · see citing works
Longitudinal Data Analysis for Discrete and Continuous Outcomes
Zeger, S. L., & Liang, K. (1986) · Biometrics · doi:10.2307/2531248 · Cited by 7,730 · see citing works
Evaluation of survival data and two new rank order statistics arising in its consideration.
Mantel, N. (1966) · PubMed · Cited by 7,516 · see citing works
Functional siRNAs and miRNAs exhibit strand bias
Khvorova, A., Reynolds, A., & Jayasena, S. D. (2003) · Cell · doi:10.1016/s0092-8674(03)00801-8 · Cited by 2,645 · see citing works
Activation of the interferon system by short-interfering RNAs
Sledz, C. A., Holko, M., de Veer, M. J., Silverman, R. H., & Williams, B. R. G. (2003) · Nature Cell Biology · doi:10.1038/ncb1038 · Cited by 1,401 · see citing works
Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA
Judge, A. D., Sood, V., Shaw, J. R., Fang, D., McClintock, K., & MacLachlan, I. (2005) · Nature Biotechnology · doi:10.1038/nbt1081 · Cited by 1,250 · see citing works
Hornung, V., Guenthner‐Biller, M., Bourquin, C., Ablasser, A., Schlee, M., Uematsu, S., Noronha, A. M., Manoharan, M., Akira, S., de Fougerolles, A., et al. (2005) · Nature Medicine · doi:10.1038/nm1191 · Cited by 1,233 · see citing works
siRNA-directed inhibition of HIV-1 infection
Novina, C. D., Murray, M. F., Dykxhoorn, D. M., Beresford, P. J., Riess, J. W., Lee, S., Collman, R. G., Lieberman, J., Shankar, P., & Sharp, P. A. (2002) · Nature Medicine · doi:10.1038/nm725 · Cited by 775 · see citing works
Self-citationInhibition of respiratory viruses by nasally administered siRNA
Bitko, V., Musiyenko, A., Shulyayeva, O., & Barik, S. (2004) · Nature Medicine · doi:10.1038/nm1164 · Cited by 725 · see citing works
Wald, A., & Link, K. (2002) · The Journal of Infectious Diseases · doi:10.1086/338231 · Cited by 689 · see citing works
Generating green fluorescent mice by germline transmission of green fluorescent ES cells
Hadjantonakis, A., Gertsenstein, M., Ikawa, M., Okabe, M., & Nagy, A. (1998) · Mechanisms of Development · doi:10.1016/s0925-4773(98)00093-8 · Cited by 483 · see citing works
Inhibition of influenza virus production in virus-infected mice by RNA interference
Ge, Q., Filip, L., Bai, A., Nguyen, T., Eisen, H. N., & Chen, J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402486101 · Cited by 444 · see citing works
Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque
Li, B.-J., Tang, Q., Cheng, D., Qin, C., Xie, F. Y., Wei, Q., Xu, J., Liu, Y., Zheng, B.-J., Woodle, M. C., et al. (2005) · Nature Medicine · doi:10.1038/nm1280 · Cited by 433 · see citing works
Human Immunodeficiency Virus Type 1 Escape from RNA Interference
Boden, D., Pusch, O., Lee, F., et al. (2003) · Journal of Virology · doi:10.1128/jvi.77.21.11531-11535.2003 · Cited by 414 · see citing works
Protection against lethal influenza virus challenge by RNA interference in vivo
Tompkins, S. M., Lo, C.-Y., Tumpey, T. M., & Epstein, S. L. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402630101 · Cited by 378 · see citing works
Zhang, W., Yang, H., Kong, X., Mohapatra, S., San-Juan-Vergara, H. G., Hellermann, G., Behera, S., Singam, R., Lockey, R. F., & Mohapatra, S. S. (2004) · Nature Medicine · doi:10.1038/nm1174 · Cited by 364 · see citing works
RNA interference and chemically modified small interfering RNAs
Manoharan, M. (2004) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2004.10.007 · Cited by 347 · see citing works
Gitlin, L., Stone, J. K., & Andino, R. (2004) · Journal of Virology · doi:10.1128/jvi.79.2.1027-1035.2005 · Cited by 235 · see citing works
Wilson, J. A., & Richardson, C. D. (2005) · Journal of Virology · doi:10.1128/jvi.79.11.7050-7058.2005 · Cited by 203 · see citing works
Lack of interferon response in animals to naked siRNAs
Heidel, J. D., Hu, S., Liu, X. F., Triche, T. J., & Davis, M. E. (2004) · Nature Biotechnology · doi:10.1038/nbt1038 · Cited by 183 · see citing works
The Prospect of Silencing Disease Using RNA Interference
Shankar, P. (2005) · JAMA · doi:10.1001/jama.293.11.1367 · Cited by 140 · see citing works
Genital herpes and human immunodeficiency virus: double trouble.
Celum, C., Levine, R., Weaver, M. R., et al. (2004) · PubMed · Cited by 138 · see citing works
Hodder, A., Simond, J.-J., & Schwery, A. (1999) · Cited by 136 · see citing works
Genetic evidence for multiple nuclear functions of the herpes simplex virus ICP8 DNA-binding protein
Gao, M., & Knipe, D. M. (1989) · Journal of Virology · doi:10.1128/jvi.63.12.5258-5267.1989 · Cited by 113 · see citing works
Self-citationMorrison, L. A., Costa, X. J. D., & Knipe, D. M. (1998) · Virology · doi:10.1006/viro.1998.9047 · Cited by 106 · see citing works
Self-citationSpang, A., Godowski, P. J., & Knipe, D. M. (1983) · Journal of Virology · doi:10.1128/jvi.45.1.332-342.1983 · Cited by 53 · see citing works
Self-citationJones, C., Taylor, T. J., & Knipe, D. M. (2000) · Virology · doi:10.1006/viro.2000.0628 · Cited by 47 · see citing works
Self-citationPilcher, H. R. (2004) · Nature · doi:10.1038/430138a · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Knocking down barriers: advances in siRNA delivery
Whitehead, K. A., Langer, R., & Anderson, D. G. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2742 · Cited by 3,115 · see citing works
RNAi-mediated gene silencing in non-human primates
Zimmermann, T. S., Lee, A. C. H., Akinc, A., Bramlage, B., Bumcrot, D., Fedoruk, M. N., Harborth, J., Heyes, J. A., Jeffs, L. B., John, M., et al. (2006) · Nature · doi:10.1038/nature04688 · Cited by 1,357 · see citing works
Strategies for silencing human disease using RNA interference
Kim, D. H., & Rossi, J. J. (2007) · Nature Reviews Genetics · doi:10.1038/nrg2006 · Cited by 1,078 · see citing works
Nanotechnology approaches for global infectious diseases
Kirtane, A. R., Verma, M., Karandikar, P., Furin, J., Langer, R., & Traverso, G. (2021) · Nature Nanotechnology · doi:10.1038/s41565-021-00866-8 · Cited by 520 · see citing works
Polymer-based nanocarriers for vaginal drug delivery
das Neves, J., Nunes, R., Machado, A., & Sarmento, B. (2015) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.12.004 · Cited by 138 · see citing works
Polymer nanoparticles encapsulating siRNA for treatment of HSV-2 genital infection
Steinbach, J. M., Weller, C. E., Booth, C. J., & Saltzman, W. M. (2012) · Journal of Controlled Release · doi:10.1016/j.jconrel.2012.06.008 · Cited by 113 · see citing works
Polymeric micelles for siRNA delivery
Falamarzian, A., Xiong, X.-B., Uludag, H., & Lavasanifar, A. (2012) · Journal of Drug Delivery Science and Technology · doi:10.1016/s1773-2247(12)50004-3 · Cited by 25 · see citing works
- Authors
- Palliser, D., Chowdhury, D., Wang, Q.-Y., Lee, S. J., Bronson, R. T., Knipe, D. M., & Lieberman, J.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Lieberman, Judy
- Venue
- Nature
- Published
- 2005-11-23
- Volume
- 439
- Issue
- 7072
- Pages
- 89-94
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1989407131
- Cited by
- 410
- References
- 29
- Citations by year
- 2025: 6 · 2024: 10 · 2023: 5 · 2022: 11 · 2021: 9 · 2020: 8 · 2019: 7 · 2018: 8 · 2017: 10 · 2016: 11 · 2015: 18 · 2014: 27 · 2013: 21 · 2012: 30
- FWCI
- 14.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- amfAR, The Foundation for AIDS Research
- Leukemia and Lymphoma Society
- National Institutes of Health
- Center for AIDS Research, University of Washington
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- siRNA, microbicides, herpes simplex virus type 2, genital herpes, RNA interference, vaginal delivery, gene silencing, sexually transmitted infections, vaginal epithelium
- MeSH terms
- Administration, Intravaginal, Animals, Cell Line, Cervix Uteri, Female, Genes, Viral, Herpes Genitalis, Inflammation, Interferons, Liposomes, Mice, Inbred BALB C, Time Factors, Vagina, Viral Proteins, Virus Replication, Herpesvirus 2, Human, Genes, Essential, Gene Silencing, RNA, Small Interfering, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
