T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice.
Evaluation of the therapeutic potential of RNAi for HIV infection has been hampered by the challenges of siRNA delivery and lack of suitable animal models. Using a delivery method for T cells, we show that siRNA treatment can dramatically suppress HIV infection. A CD7-specific single-chain antibody was conjugated to oligo-9-arginine peptide (scFvCD7-9R) for T cell-specific siRNA delivery in NOD/SCIDIL2rgamma-/- mice reconstituted with human lymphocytes (Hu-PBL) or CD34+ hematopoietic stem cells (Hu-HSC). In HIV-infected Hu-PBL mice, treatment with anti-CCR5 (viral coreceptor) and antiviral siRNAs complexed to scFvCD7-9R controlled viral replication and prevented the disease-associated CD4 T cell loss. This treatment also suppressed endogenous virus and restored CD4 T cell counts in mice reconstituted with HIV+ peripheral blood mononuclear cells. Moreover, scFvCD7-9R could deliver antiviral siRNAs to naive T cells in Hu-HSC mice and effectively suppress viremia in infected mice. Thus, siRNA therapy for HIV infection appears to be feasible in a preclinical animal model.
Kumar
Priti
P
Immune Disease Institute and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Ban
Hong-Seok
HS
Kim
Sang-Soo
SS
Wu
Haoquan
H
Pearson
Todd
T
Greiner
Dale L
DL
Laouar
Amale
A
Yao
Jiahong
J
Haridas
Viraga
V
Habiro
Katsuyoshi
K
Yang
Yong-Guang
YG
Jeong
Ji-Hoon
JH
Lee
Kuen-Yong
KY
Kim
Yong-Hee
YH
Kim
Sung Wan
SW
Peipp
Matthias
M
Fey
Georg H
GH
Manjunath
N
N
Shultz
Leonard D
LD
Lee
Sang-Kyung
SK
Shankar
Premlata
P
D000818:Animals; D019011:Antigens, CD7 / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D015658:HIV Infections / Q000235:genetics* / Q000628:therapy*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007128:Immunoglobulin Fragments / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
D019011:Antigens, CD7; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D034741:RNA, Small Interfering; D012367:RNA, Viral