Our studies provide a fundamental demonstration that inactivation of cxcr4 by treatment with X4-ZFNs rendered human CD4+ T cells resistant to infection by X4 virus strains, while CXCR4 inactivation in the context of a ccr5Δ32 homozygous background rendered cells resistant to infection by both R5 and R5X4 strains. The gene discussed is CXCR4; the disease is infection.