Theranostics 2018; 8(6):1575-1590. doi:10.7150/thno.23085 This issue Cite

Research Paper

Receptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1

Jiehua Zhou1✉, Daniel Lazar2, Haitang Li1, Xin Xia1, Sangeetha Satheesan1,4, Paige Charlins3, Denis O'Mealy2, Ramesh Akkina3, Sheena Saayman5, Marc S. Weinberg5, John J. Rossi1,4, Kevin V. Morris2✉

1. Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA.
2. Center for Gene Therapy, Beckman Research Institute of City of Hope, Duarte, CA.
3. Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO
4. Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, CA, USA
5. HIV Pathogenesis Research Unit; Department of Molecular Medicine and Hematology, School of Pathology; University of the Witwatersrand, South Africa

Citation:
Zhou J, Lazar D, Li H, Xia X, Satheesan S, Charlins P, O'Mealy D, Akkina R, Saayman S, Weinberg MS, Rossi JJ, Morris KV. Receptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1. Theranostics 2018; 8(6):1575-1590. doi:10.7150/thno.23085. https://www.thno.org/v08p1575.htm
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Abstract

Graphic abstract

Gene-based therapies represent a promising therapeutic paradigm for the treatment of HIV-1, as they have the potential to maintain sustained viral inhibition with reduced treatment interventions. Such an option may represent a long-term treatment alternative to highly active antiretroviral therapy.

Methods: We previously described a therapeutic approach, referred to as transcriptional gene silencing (TGS), whereby small noncoding RNAs directly inhibit the transcriptional activity of HIV-1 by targeting sites within the viral promoter, specifically the 5' long terminal repeat (LTR). TGS differs from traditional RNA interference (RNAi) in that it is characterized by concomitant silent-state epigenetic marks on histones and DNA. To deliver TGS-inducing RNAs, we developed functional RNA conjugates based on the previously reported dual function of the gp120 (A-1) aptamer conjugated to 27-mer Dicer-substrate anti-HIV-1 siRNA (dsiRNA), LTR-362.

Results: We demonstrate here that high levels of processed guide RNAs localize to the nucleus in infected T lymphoblastoid CEM cell line and primary human CD4+ T-cells. Treatment of the aptamer-siRNA conjugates induced TGS with an ~10-fold suppression of viral p24 levels as measured at day 12 post infection. To explore the silencing efficacy of aptamer-siRNA conjugates in vivo, HIV-1-infected humanized NOD/SCID/IL2 rγnull mice (hu-NSG) were treated with the aptamer-siRNA conjugates. Systemic delivery of the A-1-stick-LTR-362 27-mer siRNA conjugates suppressed HIV-1 infection and protected CD4+ T cell levels in viremia hu-NSG mice.

Principle conclusions: Collectively these data suggest that the gp120 aptamer-dsiRNA conjugate design is suitable for systemic delivery of small RNAs that can be used to suppress HIV-1.

Keywords: Aptamer, HIV-1, gp120, transcriptional gene silencing, RNAi


Citation styles

APA
Zhou, J., Lazar, D., Li, H., Xia, X., Satheesan, S., Charlins, P., O'Mealy, D., Akkina, R., Saayman, S., Weinberg, M.S., Rossi, J.J., Morris, K.V. (2018). Receptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1. Theranostics, 8(6), 1575-1590. https://doi.org/10.7150/thno.23085.

ACS
Zhou, J.; Lazar, D.; Li, H.; Xia, X.; Satheesan, S.; Charlins, P.; O'Mealy, D.; Akkina, R.; Saayman, S.; Weinberg, M.S.; Rossi, J.J.; Morris, K.V. Receptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1. Theranostics 2018, 8 (6), 1575-1590. DOI: 10.7150/thno.23085.

NLM
Zhou J, Lazar D, Li H, Xia X, Satheesan S, Charlins P, O'Mealy D, Akkina R, Saayman S, Weinberg MS, Rossi JJ, Morris KV. Receptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1. Theranostics 2018; 8(6):1575-1590. doi:10.7150/thno.23085. https://www.thno.org/v08p1575.htm

CSE
Zhou J, Lazar D, Li H, Xia X, Satheesan S, Charlins P, O'Mealy D, Akkina R, Saayman S, Weinberg MS, Rossi JJ, Morris KV. 2018. Receptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1. Theranostics. 8(6):1575-1590.

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