Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection

HIV-1 entry into CD4+ T cells requires binding of the virus to CD4 followed by engagement of either the C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4) coreceptor. Pharmacologic blockade or genetic inactivation of either coreceptor protects cells from infection by viruses that...

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Bibliographic Details
Published in:Blood 2014-01, Vol.123 (1), p.61-69
Main Authors: Didigu, Chuka A., Wilen, Craig B., Wang, Jianbin, Duong, Jennifer, Secreto, Anthony J., Danet-Desnoyers, Gwenn A., Riley, James L., Gregory, Phillip D., June, Carl H., Holmes, Michael C., Doms, Robert W.
Format: Article
Language:English
Subjects:
Animals
CD4-Positive T-Lymphocytes - cytology
CD4-Positive T-Lymphocytes - virology
Cell Proliferation
Endodeoxyribonucleases - metabolism
Female
HEK293 Cells
HIV Infections - immunology
HIV Infections - prevention & control
HIV Infections - therapy
HIV-1
Humans
Immunobiology
Male
Mice
Receptors, CCR5 - genetics
Receptors, Chemokine - metabolism
Receptors, CXCR4 - genetics
Zinc Fingers
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Summary:HIV-1 entry into CD4+ T cells requires binding of the virus to CD4 followed by engagement of either the C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4) coreceptor. Pharmacologic blockade or genetic inactivation of either coreceptor protects cells from infection by viruses that exclusively use the targeted coreceptor. We have used zinc-finger nucleases to drive the simultaneous genetic modification of both ccr5 and cxcr4 in primary human CD4+ T cells. These gene-modified cells proliferated normally and were resistant to both CCR5- and CXCR4-using HIV-1 in vitro. When introduced into a humanized mouse model of HIV-1 infection, these coreceptor negative cells engraft and traffic normally, and are protected from infection with CCR5- and CXCR4-using HIV-1 strains. These data suggest that simultaneous disruption of the HIV coreceptors may provide a useful approach for the long-term, drug-free treatment of established HIV-1 infections. •Zinc-finger nucleases simultaneously and permanently inactivate HIV coreceptors ccr5 and cxcr4 resulting in HIV-resistant CD4+ T cells.•These HIV-resistant cells may be used to achieve a functional cure for HIV in humans.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2013-08-521229