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Targeting lentiviral vectors to specific cell types in vivo

Yang, Lili and Bailey, Leslie and Baltimore, David and Wang, Pin (2006) Targeting lentiviral vectors to specific cell types in vivo. Proceedings of the National Academy of Sciences of the United States of America, 103 (31). pp. 11479-11484. ISSN 0027-8424. PMCID PMC1518805. https://resolver.caltech.edu/CaltechAUTHORS:YANpnas06

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Abstract

We have developed an efficient method to target lentivirus-mediated gene transduction to a desired cell type. It involves incorporation of antibody and fusogenic protein as two distinct molecules into the lentiviral surface. The fusogen is constructed by modifying viral envelope proteins, so that they lack the ability to bind to their cognate receptor but still retain the ability to trigger pH-dependent membrane fusion. Thus, the specificity of such a lentiviral vector is solely determined by the antibody, which is chosen to recognize a specific surface antigen of the desired cell type. This specific binding then induces endocytosis of the surface antigen, bringing the lentivirus into an endosome. There, the fusogen responds to the low pH environment and mediates membrane fusion, allowing the virus core to enter the cytosol. Using CD20 as a target antigen for human B cells, we have demonstrated that this targeting strategy is effective both in vitro and in intact animals. This methodology is flexible and can be extended to other forms of cell type-specific recognition to mediate targeting. The only requirement is that the antibody (or other binding protein) must be endocytosed after interaction with its cell surface-binding determinant.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.0604993103DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1518805/PubMed CentralArticle
ORCID:
AuthorORCID
Baltimore, David0000-0001-8723-8190
Additional Information:© 2006 by the National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by David Baltimore, June 15, 2006. We thank Dr. James Strauss (California Institute of Technology, Pasadena, CA), Drs. Paula Cannon and Donald Kohn (Childrens Hospital, Los Angeles, CA), and H.-D. Klenk (Philipps University, Marburg, Germany) for providing reagents; Rochelle Diamond and Stephanie Adams for help with cell sorting; and Dr. Markus Covert and Eric Santiestevan for critical reading of this manuscript. This research was generously supported by the Skirball Foundation, a grant from the Bill and Melinda Gates Foundation through the Grand Challenges in Global Health Initiative, and a University of Southern California startup fund. Author contributions: L.Y., D.B., and P.W. designed research; L.Y., L.B., and P.W. performed research; L.Y. and P.W. contributed new reagents/analytic tools; L.Y., L.B., D.B., and P.W. analyzed data; and L.Y., L.A.B., D.B., and P.W. wrote the paper. Conflict of interest statement: No conflicts declared. We have observed that this method can be exploited to target dendritic cells using a membrane-bound monoclonal antibody against the DEC-205 receptor. In addition, we found that incorporation of a membrane-bound form of stem cell factor could target c-kit-positive cells.
Funders:
Funding AgencyGrant Number
Skirball FoundationUNSPECIFIED
Bill and Melinda Gates FoundationUNSPECIFIED
University of Southern CaliforniaUNSPECIFIED
Subject Keywords:antibody; gene therapy; lentivirus; retrovirus; targeted gene delivery
Issue or Number:31
PubMed Central ID:PMC1518805
Record Number:CaltechAUTHORS:YANpnas06
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:YANpnas06
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:4258
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:09 Aug 2006
Last Modified:16 Apr 2020 23:46

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