T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice

Priti Kumar; Hong Seok Ban; Sang Soo Kim; Haoquan Wu; Todd Pearson; Dale L. Greiner; Amale Laouar; Jiahong Yao; Viraga Haridas; Katsuyoshi Habiro; Yong Guang Yang; Ji Hoon Jeong; Kuen Yong Lee; Yong Hee Kim; Sung Wan Kim; Matthias Peipp; Georg H. Fey; N. Manjunath; Leonard D. Shultz; Sang Kyung Lee; Premlata Shankar

doi:10.1016/j.cell.2008.06.034

T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice

Priti Kumar, Hong Seok Ban, Sang Soo Kim, Haoquan Wu, Todd Pearson, Dale L. Greiner, Amale Laouar, Jiahong Yao, Viraga Haridas, Katsuyoshi Habiro, Yong Guang Yang, Ji Hoon Jeong, Kuen Yong Lee, Yong Hee Kim, Sung Wan Kim, Matthias Peipp, Georg H. Fey, N. Manjunath, Leonard D. Shultz, Sang Kyung LeePremlata Shankar

Research output: Contribution to journal › Article › peer-review

Abstract

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/SCIDIL2rγ^-/- 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.

Original language	English (US)
Pages (from-to)	577-586
Number of pages	10
Journal	Cell
Volume	134
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2008.06.034
State	Published - Aug 22 2008
Externally published	Yes

Keywords

CELLIMMUNO
HUMDISEASE

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Online availability

10.1016/j.cell.2008.06.034

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Kumar, P., Ban, H. S., Kim, S. S., Wu, H., Pearson, T., Greiner, D. L., Laouar, A., Yao, J., Haridas, V., Habiro, K., Yang, Y. G., Jeong, J. H., Lee, K. Y., Kim, Y. H., Kim, S. W., Peipp, M., Fey, G. H., Manjunath, N., Shultz, L. D., ... Shankar, P. (2008). T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice. Cell, 134(4), 577-586. https://doi.org/10.1016/j.cell.2008.06.034

Kumar, P, Ban, HS, Kim, SS, Wu, H, Pearson, T, Greiner, DL, Laouar, A, Yao, J, Haridas, V, Habiro, K, Yang, YG, Jeong, JH, Lee, KY, Kim, YH, Kim, SW, Peipp, M, Fey, GH, Manjunath, N, Shultz, LD, Lee, SK & Shankar, P 2008, 'T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice', Cell, vol. 134, no. 4, pp. 577-586. https://doi.org/10.1016/j.cell.2008.06.034

@article{437a829ed93045098676b0717f53d97d,

title = "T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice",

abstract = "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/SCIDIL2rγ-/- 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.",

keywords = "CELLIMMUNO, HUMDISEASE",

author = "Priti Kumar and Ban, {Hong Seok} and Kim, {Sang Soo} and Haoquan Wu and Todd Pearson and Greiner, {Dale L.} and Amale Laouar and Jiahong Yao and Viraga Haridas and Katsuyoshi Habiro and Yang, {Yong Guang} and Jeong, {Ji Hoon} and Lee, {Kuen Yong} and Kim, {Yong Hee} and Kim, {Sung Wan} and Matthias Peipp and Fey, {Georg H.} and N. Manjunath and Shultz, {Leonard D.} and Lee, {Sang Kyung} and Premlata Shankar",

note = "Funding Information: We thank Changseon Choi and Nahyun Kim for technical assistance and Luke Jasenosky for editing the manuscript. This work was supported by the following grants: NIH/National Institute of Allergy and Infectious Diseases RO1 A1071882 and R21 AI06532 to P.S., Korea Ministry of Education and Science Technology R01-2006-000-10506-0 and F104AA010005-07A0101-00510 and Seoul R&BD CR070027 to S.K.L., CFAR fellowship P30 A060354 to P.K., NIH/NIAID Autoimmunity Prevention Center grant to D.L.G., NIH CA34196 to L.D.S., Juvenile Diabetes Research Foundation to D.L.G., L.D.S., and T.P., MOEHRD KRF-2006-352-D00070 to S.S.K., NIH/NIAID UO1 AI075419 to M.N., a Wilhelm Sander Foundation research grant to G.H.F, and the Seoul Fellowship to H.S.B. ",

year = "2008",

month = aug,

day = "22",

doi = "10.1016/j.cell.2008.06.034",

language = "English (US)",

volume = "134",

pages = "577--586",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "4",

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TY - JOUR

T1 - T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice

AU - Kumar, Priti

AU - Ban, Hong Seok

AU - Kim, Sang Soo

AU - Wu, Haoquan

AU - Pearson, Todd

AU - Greiner, Dale L.

AU - Laouar, Amale

AU - Yao, Jiahong

AU - Haridas, Viraga

AU - Habiro, Katsuyoshi

AU - Yang, Yong Guang

AU - Jeong, Ji Hoon

AU - Lee, Kuen Yong

AU - Kim, Yong Hee

AU - Kim, Sung Wan

AU - Peipp, Matthias

AU - Fey, Georg H.

AU - Manjunath, N.

AU - Shultz, Leonard D.

AU - Lee, Sang Kyung

AU - Shankar, Premlata

N1 - Funding Information: We thank Changseon Choi and Nahyun Kim for technical assistance and Luke Jasenosky for editing the manuscript. This work was supported by the following grants: NIH/National Institute of Allergy and Infectious Diseases RO1 A1071882 and R21 AI06532 to P.S., Korea Ministry of Education and Science Technology R01-2006-000-10506-0 and F104AA010005-07A0101-00510 and Seoul R&BD CR070027 to S.K.L., CFAR fellowship P30 A060354 to P.K., NIH/NIAID Autoimmunity Prevention Center grant to D.L.G., NIH CA34196 to L.D.S., Juvenile Diabetes Research Foundation to D.L.G., L.D.S., and T.P., MOEHRD KRF-2006-352-D00070 to S.S.K., NIH/NIAID UO1 AI075419 to M.N., a Wilhelm Sander Foundation research grant to G.H.F, and the Seoul Fellowship to H.S.B.

PY - 2008/8/22

Y1 - 2008/8/22

N2 - 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/SCIDIL2rγ-/- 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.

AB - 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/SCIDIL2rγ-/- 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.

KW - CELLIMMUNO

KW - HUMDISEASE

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UR - http://www.scopus.com/inward/citedby.url?scp=49549117077&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2008.06.034

DO - 10.1016/j.cell.2008.06.034

M3 - Article

C2 - 18691745

AN - SCOPUS:49549117077

SN - 0092-8674

VL - 134

SP - 577

EP - 586

JO - Cell

JF - Cell

IS - 4

ER -

T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice

Abstract

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