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176 Exploring the Potential of CCR5 and CXCR4 Modified CD4 T Cells to Target the HIV-1 Reservoir

Tebas, P; Wilsen, C; Doms, R; Hoxie, J; Gregory, P; Holmes, M; June, C

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 73
doi: 10.1097/01.qai.0000397359.53545.66

University of Pennsylvania, Phildelphia, PA and Sangamo Biosciences, Richmond, CA

Viruses that use CCR5 (R5 strains) are the major cause of new infections, while viruses that evolve the ability to use CXCR4 can arise later in infection and are associated with accelerated disease progression. Natural resistance to HIV infection can be conferred by the loss of CCR5 due to a Δ32-ccr5 polymorphism that makes individuals homozygous for this allele CCR5-negative. Heterozygosity for Δ32-ccr5 resuls in slower disease progression in those who become infected. We have conferred genetic resistance to HIV infection through the targeted, permanent disruption of the ccr5 gene in human T cells through the use of high specific zinc-finger nucleases (ZFNs). In vitro, cells with disrupted ccr5 grow normally, are resistant to infection by R5 virus strains, but are sensitive to X4 virus strains. We have recently applied the ZFN gene knockout approach to the HIV co-receptor CXCR4 and find that this also results in a permanent disruption of CXCR4, and resistance to infection with X4-tropic HIV-1. Primary T cells with knockout of both CCR5 and CXCR4 have been created and these T cells exhibit a robust resistance to all tested strains of HIV-1. The current status of the phase 1trial testing the safety and feasibility of CCR5 disruption using autologous CD4 T cells treated with CCR5 specific ZFNs will be reviewed.

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