RNAi-mediated CCR5 Silencing by LFA-1-targeted Nanoparticles Prevents HIV Infection in BLT Mice
| Autor: | Priti Kumar, Yong-Guang Yang, Sandesh Subramanya, Premlata Shankar, Huaquan Wu, Motomu Shimaoka, Katsuyoshi Habiro, Deshratan Asthana, Sang-Soo Kim, N. Manjunath, Dan Peer |
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| Rok vydání: | 2010 |
| Předmět: |
Small interfering RNA
Receptors CCR5 Viral pathogenesis HIV Infections Biology Mice 03 medical and health sciences 0302 clinical medicine In vivo RNA interference Drug Discovery Leukocytes Genetics Animals Gene silencing Gene Silencing Lymphocyte function-associated antigen 1 RNA Small Interfering Molecular Biology 030304 developmental biology Pharmacology 0303 health sciences Gene knockdown Reverse Transcriptase Polymerase Chain Reaction Original Articles Virology Lymphocyte Function-Associated Antigen-1 3. Good health 030220 oncology & carcinogenesis Liposomes Humanized mouse Nanoparticles Molecular Medicine RNA Interference |
| Zdroj: | Molecular Therapy. 18(2):370-376 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2009.271 |
| Popis: | RNA interference (RNAi)-mediated knockdown of gene expression offers a novel treatment strategy for human immunodeficiency virus (HIV) infection. However, the major hurdle for clinical use is a practical strategy for small interfering RNA (siRNA) delivery to the multiple immune cell types important in viral pathogenesis. We have developed a novel immunoliposome method targeting the lymphocyte function-associated antigen-1 (LFA-1) integrin expressed on all leukocytes and evaluated it for systemic delivery of siRNA in a humanized mouse model. We show that in vivo administration of the LFA-1 integrin-targeted and stabilized nanoparticles (LFA-1 I-tsNPs) results in selective uptake of siRNA by T cells and macrophages, the prime targets of HIV. Further, in vivo administration of anti-CCR5 siRNA/LFA-1 I-tsNPs resulted in leukocyte-specific gene silencing that was sustained for 10 days. Finally, humanized mice challenged with HIV after anti-CCR5 siRNA treatment showed enhanced resistance to infection as assessed by the reduction in plasma viral load and disease-associated CD4 T-cell loss. This study demonstrates the potential in vivo applicability of LFA-1-directed siRNA delivery as anti-HIV prophylaxis. |
| Databáze: | OpenAIRE |
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