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PK Dash, R Kaminski, R Bella, H Su, S Mathews, TM Ahooyi, C Chen, P Mancuso, R Sariyer, P Ferrante, M Donadoni, JA Robinson, B Sillman, Z Lin, JR Hilaire, M Banoub, M Elango, N Gautam, RL Mosley, LY Poluektova, J McMillan, AN Bade, S Gorantla, IK Sariyer, TH Burdo, WB Young, S Amini, J Gordon, JM Jacobson, B Edagwa, K Khalili and HE Gendelman
Abstract
Elimination of HIV-1 requires clearance and removal of integrated proviral DNA from infected cells and tissues. Here, sequential long-acting slow-effective release antiviral therapy (LASER ART) and CRISPR-Cas9 demonstrate viral clearance in latent infectious reservoirs in HIV-1 infected humanized mice. HIV-1 subgenomic DNA fragments, spanning the long terminal repeats and the Gag gene, are excised in vivo, resulting in elimination of integrated proviral DNA; virus is not detected in blood, lymphoid tissue, bone marrow and brain by nested and digital-droplet PCR as well as RNAscope tests. No CRISPR-Cas9 mediated off-target effects are detected. Adoptive transfer of human immunocytes from dual treated, virus-free animals to uninfected humanized mice fails to produce infectious progeny virus. In contrast, HIV-1 is readily detected following sole LASER ART or CRISPR-Cas9 treatment. These data provide proof-of-concept that permanent viral elimination is possible.
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