RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice

Sang Soo Kim, Dan Peer, Priti Kumar, Sandesh Subramanya, Huaquan Wu, Deshratan Asthana, Katsuyoshi Habiro, Yong Guang Yang, N. Manjunath, Motomu Shimaoka, Premlata Shankar

Research output: Contribution to journalArticle

158 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)370-376
Number of pages7
JournalMolecular Therapy
Volume18
Issue number2
DOIs
StatePublished - Feb 1 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Kim, S. S., Peer, D., Kumar, P., Subramanya, S., Wu, H., Asthana, D., Habiro, K., Yang, Y. G., Manjunath, N., Shimaoka, M., & Shankar, P. (2010). RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice. Molecular Therapy, 18(2), 370-376. https://doi.org/10.1038/mt.2009.271