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

Abstract

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.

• Authors: Chuka A Didigu, Craig B Wilen, Jianbin Wang, Jennifer Duong, Anthony J Secreto, Gwenn A Danet-Desnoyers, James L Riley, Phillip D Gregory, Carl H June, Michael C Holmes, Robert W Doms
• Journal: Blood (Blood) Vol. 123 Issue 1 Pg. 61-9 (Jan 02 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24162716 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CCR5 protein, human
• CXCR4 protein, human
• Receptors, CCR5
• Receptors, CXCR4
• Receptors, Chemokine
• Endodeoxyribonucleases

Topics

• Animals
• CD4-Positive T-Lymphocytes (cytology, virology)
• Cell Proliferation
• Endodeoxyribonucleases (metabolism)
• Female
• HEK293 Cells
• HIV Infections (immunology, prevention & control, therapy)
• HIV-1
• Humans
• Male
• Mice
• Receptors, CCR5 (genetics)
• Receptors, CXCR4 (genetics)
• Receptors, Chemokine (metabolism)
• Zinc Fingers