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Dash PK , Kaminski R , Bella R , Su H , Mathews S , Ahooyi TM , Chen C , Mancuso P , Sariyer R , Ferrante P , Donadoni M , Robinson JA , Sillman B , Lin Z , Hilaire JR , Banoub M , Elango M , Gautam N , Mosley RL , Poluektova LY , McMillan J , Bade AN , Gorantla S , Sariyer IK , Burdo TH , Young WB , Amini S , Gordon J , Jacobson JM , Edagwa B , Khalili K , Gendelman HE
Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice
Nat Commun. 2019 Jul 2;10(1) :2753
PMID: 31266936    PMCID: PMC6606613    URL: https://www.ncbi.nlm.nih.gov/pubmed/31266936
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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.
Notes
2041-1723 Dash, Prasanta K Kaminski, Rafal Bella, Ramona Su, Hang Mathews, Saumi Ahooyi, Taha M Chen, Chen Mancuso, Pietro Sariyer, Rahsan Ferrante, Pasquale Donadoni, Martina Robinson, Jake A Sillman, Brady Lin, Zhiyi Hilaire, James R Banoub, Mary Elango, Monalisha Gautam, Nagsen Mosley, R Lee Poluektova, Larisa Y McMillan, JoEllyn Bade, Aditya N Gorantla, Santhi Sariyer, Ilker K Burdo, Tricia H Young, Won-Bin Amini, Shohreh Gordon, Jennifer Jacobson, Jeffrey M Edagwa, Benson Khalili, Kamel Gendelman, Howard E P01 NS043985/NS/NINDS NIH HHS/United States P01 DA028555/DA/NIDA NIH HHS/United States R01NS036126/U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) P30MH062261/U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01DA042706/U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) P01DA037830/U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) R01MH110360/U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) P30MH092177/U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01NS034239/U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) Journal Article England Nat Commun. 2019 Jul 2;10(1):2753. doi: 10.1038/s41467-019-10366-y.