SignificanceLong-acting antiretroviral drugs suppress viral replication in humanized mice. When administered CRISPR-mediated CCR5 and HIV-1LTR-Gag CRISPR editing the treatments resulted in the elimination of HIV-1 proviral DNA in lymphoid, bone marrow, and central nervous system tissues in 58% of the infected animals. Combinatorial CRISPR therapies proved statistically superior compared to single therapy for this HIV-1 cure strategy.