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Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5

Qin, Xiao-Feng and An, Dong Sung and Chen, Irvin S. Y. and Baltimore, David (2003) Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proceedings of the National Academy of Sciences of the United States of America, 100 (1). pp. 183-188. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:QINpnas03

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Abstract

Double-stranded RNAs approximate to 21 nucleotides long [small interfering RNA (siRNA)] are recognized as powerful reagents to reduce the expression of specific genes. To use them as reagents to protect cells against viral infection, effective methods for introducing siRNAs into primary cells are required. Here, we describe success in constructing a lentivirus-based vector to introduce siRNAs against the HIV-1 coreceptor, CCR5, into human peripheral blood T lymphocytes. With high-titer vector stocks, >40% of the peripheral blood T lymphocytes could be transduced, and the expression of a potent CCR5-siRNA resulted in up to 10-fold inhibition of CCR5 expression on the cell surface over a period of 2 weeks in the absence of selection. In contrast, the expression of another major HIV-1 coreceptor, CXCR4, was not affected. Importantly, blocking CCR5 expression by siRNAs provided a substantial protection for the lymphocyte populations from CCR5-tropic HIV-1 virus infection, dropping infected cells by 3- to 7-fold; only a minimal effect on infection by a CXCR4-tropic virus was observed. Thus, our studies demonstrate the feasibility and potential of lentiviral vector-mediated delivery of siRNAs as a general means of intracellular immunization for the treatment of HIV-1 and other viral diseases.


Item Type:Article
Additional Information:Copyright © 2003 by the National Academy of Sciences. Contributed by David Baltimore, November 11, 2002. We thank Carlos Lois, Yi-ming Xie, Si Hua Mao, Vaheideh Gudeman, and Kathie Grovit-Ferbas for reagents and helpful discussions. This work was supported by grants from the National Institutes of Health to D.B. (AI42549-04) and I.S.Y.C. (AI39975-05 and AI28697). X.-F.Q. was supported by Damon Runyon–Walter Winchell Fellowship DRG-1568. X.-F.Q. and D.S.A. contributed equally to this work.
Subject Keywords:human-immunodeficiency-virus, macrophage-tropic HIV-1, disease progression, gene-therapy, intracellular immunization, deletion allele, viral phenotype, in-vivo, type-1, receptor
Record Number:CaltechAUTHORS:QINpnas03
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:QINpnas03
Alternative URL:http://dx.doi.org/10.1073/pnas.232688199
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:877
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:03 Nov 2005
Last Modified:26 Dec 2012 08:41

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