RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice.
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.
Kim
Sang-Soo
SS
Department of Biomedical Sciences, Center of Excellence for Infectious Diseases, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905, USA.
Peer
Dan
D
Kumar
Priti
P
Subramanya
Sandesh
S
Wu
Huaquan
H
Asthana
Deshratan
D
Habiro
Katsuyoshi
K
Yang
Yong-Guang
YG
Manjunath
N
N
Shimaoka
Motomu
M
Shankar
Premlata
P
D000818:Animals; D020868:Gene Silencing / Q000502:physiology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D007962:Leukocytes / Q000378:metabolism; D008081:Liposomes / Q000627:therapeutic use; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D053758:Nanoparticles / Q000627:therapeutic use*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology*; D019713:Receptors, CCR5 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008081:Liposomes; D016169:Lymphocyte Function-Associated Antigen-1; D034741:RNA, Small Interfering; D019713:Receptors, CCR5