Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice

Prasanta K. Dash, Rafal Kaminski, Ramona Bella, Hang Su, Saumi Mathews, Taha M. Ahooyi, Chen Chen, Pietro Mancuso, Rahsan Sariyer, Pasquale Ferrante, Martina Donadoni, Jake A. Robinson, Brady Sillman, Zhiyi Lin, James R. Hilaire, Mary Banoub, Monalisha Elango, Nagsen Gautam, R. Lee Mosley, Larisa Y. Poluektova, JoEllyn McMillan, Aditya N. Bade, Santhi Gorantla, Ilker K. Sariyer, Tricia H. Burdo, Won-Bin Young, Shohreh Amini, Jennifer Gordon, Jeffrey M. Jacobson, Benson Edagwa, Kamel Khalili () and Howard E. Gendelman ()
Additional contact information
Prasanta K. Dash: University of Nebraska Medical Center
Rafal Kaminski: Lewis Katz School of Medicine at Temple University
Ramona Bella: Lewis Katz School of Medicine at Temple University
Hang Su: University of Nebraska Medical Center
Saumi Mathews: University of Nebraska Medical Center
Taha M. Ahooyi: Lewis Katz School of Medicine at Temple University
Chen Chen: Lewis Katz School of Medicine at Temple University
Pietro Mancuso: Lewis Katz School of Medicine at Temple University
Rahsan Sariyer: Lewis Katz School of Medicine at Temple University
Pasquale Ferrante: Lewis Katz School of Medicine at Temple University
Martina Donadoni: Lewis Katz School of Medicine at Temple University
Jake A. Robinson: Lewis Katz School of Medicine at Temple University
Brady Sillman: University of Nebraska Medical Center
Zhiyi Lin: University of Nebraska Medical Center
James R. Hilaire: University of Nebraska Medical Center
Mary Banoub: University of Nebraska Medical Center
Monalisha Elango: University of Nebraska Medical Center
Nagsen Gautam: College of Pharmacy, University of Nebraska Medical Center
R. Lee Mosley: University of Nebraska Medical Center
Larisa Y. Poluektova: University of Nebraska Medical Center
JoEllyn McMillan: University of Nebraska Medical Center
Aditya N. Bade: University of Nebraska Medical Center
Santhi Gorantla: University of Nebraska Medical Center
Ilker K. Sariyer: Lewis Katz School of Medicine at Temple University
Tricia H. Burdo: Lewis Katz School of Medicine at Temple University
Won-Bin Young: Lewis Katz School of Medicine at Temple University
Shohreh Amini: Lewis Katz School of Medicine at Temple University
Jennifer Gordon: Lewis Katz School of Medicine at Temple University
Jeffrey M. Jacobson: Lewis Katz School of Medicine at Temple University
Benson Edagwa: University of Nebraska Medical Center
Kamel Khalili: Lewis Katz School of Medicine at Temple University
Howard E. Gendelman: University of Nebraska Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-20

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10366-y

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