Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice
Identifieur interne : 000758 ( Ncbi/Merge ); précédent : 000757; suivant : 000759Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice
Auteurs : Prasanta K. Dash [États-Unis] ; Rafal Kaminski [États-Unis] ; Ramona Bella [États-Unis] ; Hang Su [États-Unis] ; Saumi Mathews [États-Unis] ; Taha M. Ahooyi [États-Unis] ; Chen Chen [États-Unis] ; Pietro Mancuso [États-Unis] ; Rahsan Sariyer [États-Unis] ; Pasquale Ferrante [États-Unis] ; Martina Donadoni [États-Unis] ; Jake A. Robinson [États-Unis] ; Brady Sillman [États-Unis] ; Zhiyi Lin [États-Unis] ; James R. Hilaire [États-Unis] ; Mary Banoub [États-Unis] ; Monalisha Elango [États-Unis] ; Nagsen Gautam [États-Unis] ; R. Lee Mosley [États-Unis] ; Larisa Y. Poluektova [États-Unis] ; Joellyn Mcmillan [États-Unis] ; Aditya N. Bade [États-Unis] ; Santhi Gorantla [États-Unis] ; Ilker K. Sariyer [États-Unis] ; Tricia H. Burdo [États-Unis] ; Won-Bin Young [États-Unis] ; Shohreh Amini [États-Unis] ; Jennifer Gordon [États-Unis] ; Jeffrey M. Jacobson [États-Unis] ; Benson Edagwa [États-Unis] ; Kamel Khalili [États-Unis] ; Howard E. Gendelman [États-Unis]Source :
- Nature Communications [ 2041-1723 ] ; 2019.
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.
Url:
DOI: 10.1038/s41467-019-10366-y
PubMed: 31266936
PubMed Central: 6606613
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Poluektova</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Mcmillan, Joellyn" sort="Mcmillan, Joellyn" uniqKey="Mcmillan J" first="Joellyn" last="Mcmillan">Joellyn Mcmillan</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Bade, Aditya N" sort="Bade, Aditya N" uniqKey="Bade A" first="Aditya N." last="Bade">Aditya N. Bade</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Gorantla, Santhi" sort="Gorantla, Santhi" uniqKey="Gorantla S" first="Santhi" last="Gorantla">Santhi Gorantla</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Sariyer, Ilker K" sort="Sariyer, Ilker K" uniqKey="Sariyer I" first="Ilker K." last="Sariyer">Ilker K. 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Burdo</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Young, Won Bin" sort="Young, Won Bin" uniqKey="Young W" first="Won-Bin" last="Young">Won-Bin Young</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Amini, Shohreh" sort="Amini, Shohreh" uniqKey="Amini S" first="Shohreh" last="Amini">Shohreh Amini</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Gordon, Jennifer" sort="Gordon, Jennifer" uniqKey="Gordon J" first="Jennifer" last="Gordon">Jennifer Gordon</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Jacobson, Jeffrey M" sort="Jacobson, Jeffrey M" uniqKey="Jacobson J" first="Jeffrey M." last="Jacobson">Jeffrey M. Jacobson</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Edagwa, Benson" sort="Edagwa, Benson" uniqKey="Edagwa B" first="Benson" last="Edagwa">Benson Edagwa</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Khalili, Kamel" sort="Khalili, Kamel" uniqKey="Khalili K" first="Kamel" last="Khalili">Kamel Khalili</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Gendelman, Howard E" sort="Gendelman, Howard E" uniqKey="Gendelman H" first="Howard E." last="Gendelman">Howard E. Gendelman</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31266936</idno><idno type="pmc">6606613</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606613</idno><idno type="RBID">PMC:6606613</idno><idno type="doi">10.1038/s41467-019-10366-y</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000143</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000143</idno><idno type="wicri:Area/Pmc/Curation">000143</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000143</idno><idno type="wicri:Area/Pmc/Checkpoint">000393</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000393</idno><idno type="wicri:Area/Ncbi/Merge">000758</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice</title><author><name sortKey="Dash, Prasanta K" sort="Dash, Prasanta K" uniqKey="Dash P" first="Prasanta K." last="Dash">Prasanta K. Dash</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Kaminski, Rafal" sort="Kaminski, Rafal" uniqKey="Kaminski R" first="Rafal" last="Kaminski">Rafal Kaminski</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Bella, Ramona" sort="Bella, Ramona" uniqKey="Bella R" first="Ramona" last="Bella">Ramona Bella</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Su, Hang" sort="Su, Hang" uniqKey="Su H" first="Hang" last="Su">Hang Su</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Mathews, Saumi" sort="Mathews, Saumi" uniqKey="Mathews S" first="Saumi" last="Mathews">Saumi Mathews</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Ahooyi, Taha M" sort="Ahooyi, Taha M" uniqKey="Ahooyi T" first="Taha M." last="Ahooyi">Taha M. Ahooyi</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Chen, Chen" sort="Chen, Chen" uniqKey="Chen C" first="Chen" last="Chen">Chen Chen</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Mancuso, Pietro" sort="Mancuso, Pietro" uniqKey="Mancuso P" first="Pietro" last="Mancuso">Pietro Mancuso</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Sariyer, Rahsan" sort="Sariyer, Rahsan" uniqKey="Sariyer R" first="Rahsan" last="Sariyer">Rahsan Sariyer</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Ferrante, Pasquale" sort="Ferrante, Pasquale" uniqKey="Ferrante P" first="Pasquale" last="Ferrante">Pasquale Ferrante</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Donadoni, Martina" sort="Donadoni, Martina" uniqKey="Donadoni M" first="Martina" last="Donadoni">Martina Donadoni</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Robinson, Jake A" sort="Robinson, Jake A" uniqKey="Robinson J" first="Jake A." last="Robinson">Jake A. Robinson</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Sillman, Brady" sort="Sillman, Brady" uniqKey="Sillman B" first="Brady" last="Sillman">Brady Sillman</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Lin, Zhiyi" sort="Lin, Zhiyi" uniqKey="Lin Z" first="Zhiyi" last="Lin">Zhiyi Lin</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Hilaire, James R" sort="Hilaire, James R" uniqKey="Hilaire J" first="James R." last="Hilaire">James R. Hilaire</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Banoub, Mary" sort="Banoub, Mary" uniqKey="Banoub M" first="Mary" last="Banoub">Mary Banoub</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Elango, Monalisha" sort="Elango, Monalisha" uniqKey="Elango M" first="Monalisha" last="Elango">Monalisha Elango</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Gautam, Nagsen" sort="Gautam, Nagsen" uniqKey="Gautam N" first="Nagsen" last="Gautam">Nagsen Gautam</name><affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmaceutical Sciences,</institution><institution>College of Pharmacy, University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Mosley, R Lee" sort="Mosley, R Lee" uniqKey="Mosley R" first="R. Lee" last="Mosley">R. Lee Mosley</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Poluektova, Larisa Y" sort="Poluektova, Larisa Y" uniqKey="Poluektova L" first="Larisa Y." last="Poluektova">Larisa Y. Poluektova</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Mcmillan, Joellyn" sort="Mcmillan, Joellyn" uniqKey="Mcmillan J" first="Joellyn" last="Mcmillan">Joellyn Mcmillan</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Bade, Aditya N" sort="Bade, Aditya N" uniqKey="Bade A" first="Aditya N." last="Bade">Aditya N. Bade</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Gorantla, Santhi" sort="Gorantla, Santhi" uniqKey="Gorantla S" first="Santhi" last="Gorantla">Santhi Gorantla</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Sariyer, Ilker K" sort="Sariyer, Ilker K" uniqKey="Sariyer I" first="Ilker K." last="Sariyer">Ilker K. Sariyer</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Burdo, Tricia H" sort="Burdo, Tricia H" uniqKey="Burdo T" first="Tricia H." last="Burdo">Tricia H. Burdo</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Young, Won Bin" sort="Young, Won Bin" uniqKey="Young W" first="Won-Bin" last="Young">Won-Bin Young</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Amini, Shohreh" sort="Amini, Shohreh" uniqKey="Amini S" first="Shohreh" last="Amini">Shohreh Amini</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Gordon, Jennifer" sort="Gordon, Jennifer" uniqKey="Gordon J" first="Jennifer" last="Gordon">Jennifer Gordon</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Jacobson, Jeffrey M" sort="Jacobson, Jeffrey M" uniqKey="Jacobson J" first="Jeffrey M." last="Jacobson">Jeffrey M. Jacobson</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Edagwa, Benson" sort="Edagwa, Benson" uniqKey="Edagwa B" first="Benson" last="Edagwa">Benson Edagwa</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author><author><name sortKey="Khalili, Kamel" sort="Khalili, Kamel" uniqKey="Khalili K" first="Kamel" last="Khalili">Kamel Khalili</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Gendelman, Howard E" sort="Gendelman, Howard E" uniqKey="Gendelman H" first="Howard E." last="Gendelman">Howard E. Gendelman</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Nebraska</region></placeName><wicri:cityArea>Omaha</wicri:cityArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">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. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31266936</article-id><article-id pub-id-type="pmc">6606613</article-id><article-id pub-id-type="publisher-id">10366</article-id><article-id pub-id-type="doi">10.1038/s41467-019-10366-y</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Dash</surname><given-names>Prasanta K.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Kaminski</surname><given-names>Rafal</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Bella</surname><given-names>Ramona</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Su</surname><given-names>Hang</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Mathews</surname><given-names>Saumi</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ahooyi</surname><given-names>Taha M.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Chen</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Mancuso</surname><given-names>Pietro</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Sariyer</surname><given-names>Rahsan</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ferrante</surname><given-names>Pasquale</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Donadoni</surname><given-names>Martina</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Robinson</surname><given-names>Jake A.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Sillman</surname><given-names>Brady</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lin</surname><given-names>Zhiyi</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hilaire</surname><given-names>James R.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Banoub</surname><given-names>Mary</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Elango</surname><given-names>Monalisha</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gautam</surname><given-names>Nagsen</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Mosley</surname><given-names>R. Lee</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Poluektova</surname><given-names>Larisa Y.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>McMillan</surname><given-names>JoEllyn</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Bade</surname><given-names>Aditya N.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gorantla</surname><given-names>Santhi</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sariyer</surname><given-names>Ilker K.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Burdo</surname><given-names>Tricia H.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Young</surname><given-names>Won-Bin</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Amini</surname><given-names>Shohreh</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Gordon</surname><given-names>Jennifer</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Jacobson</surname><given-names>Jeffrey M.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Edagwa</surname><given-names>Benson</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Khalili</surname><given-names>Kamel</given-names></name><address><email>kamel.khalili@temple.edu</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Gendelman</surname><given-names>Howard E.</given-names></name><address><email>hegendel@unmc.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmacology and Experimental Neuroscience,</institution><institution>University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2248 3398</institution-id><institution-id institution-id-type="GRID">grid.264727.2</institution-id><institution>Department of Neuroscience,</institution><institution>Lewis Katz School of Medicine at Temple University,</institution></institution-wrap>Philadelphia, PA 19115 USA</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0666 4105</institution-id><institution-id institution-id-type="GRID">grid.266813.8</institution-id><institution>Department of Pharmaceutical Sciences,</institution><institution>College of Pharmacy, University of Nebraska Medical Center,</institution></institution-wrap>Omaha, NE 68198-5880 USA</aff></contrib-group><pub-date pub-type="epub"><day>2</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>2</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>10</volume><elocation-id>2753</elocation-id><history><date date-type="received"><day>15</day><month>11</month><year>2018</year></date><date date-type="accepted"><day>22</day><month>4</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">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.</p></abstract><abstract id="Abs2" abstract-type="web-summary"><p id="Par2">Here, the authors show that sequential treatment with long-acting slow-effective release ART and AAV9- based delivery of CRISPR-Cas9 results in undetectable levels of virus and integrated DNA in a subset of humanized HIV-1 infected mice. This proof-of-concept study suggests that HIV-1 elimination is possible.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>CRISPR-Cas9 genome editing</kwd><kwd>Antivirals</kwd><kwd>HIV infections</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100000025</institution-id><institution>U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)</institution></institution-wrap></funding-source><award-id>P30MH092177</award-id><award-id>R01MH110360</award-id><award-id>P30MH062261</award-id><principal-award-recipient><name><surname>Khalili</surname><given-names>Kamel</given-names></name><name><surname>Gendelman</surname><given-names>Howard E.</given-names></name></principal-award-recipient></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100000026</institution-id><institution>U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)</institution></institution-wrap></funding-source><award-id>P01DA037830</award-id><award-id>R01DA042706</award-id><principal-award-recipient><name><surname>Khalili</surname><given-names>Kamel</given-names></name></principal-award-recipient></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100000065</institution-id><institution>U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)</institution></institution-wrap></funding-source><award-id>R01NS036126</award-id><award-id>R01NS034239</award-id><principal-award-recipient><name><surname>Gendelman</surname><given-names>Howard E.</given-names></name></principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>États-Unis</li></country><region><li>Nebraska</li><li>Pennsylvanie</li></region></list><tree><country name="États-Unis"><region name="Nebraska"><name sortKey="Dash, Prasanta K" sort="Dash, Prasanta K" uniqKey="Dash P" first="Prasanta K." last="Dash">Prasanta K. Dash</name></region><name sortKey="Ahooyi, Taha M" sort="Ahooyi, Taha M" uniqKey="Ahooyi T" first="Taha M." last="Ahooyi">Taha M. Ahooyi</name><name sortKey="Amini, Shohreh" sort="Amini, Shohreh" uniqKey="Amini S" first="Shohreh" last="Amini">Shohreh Amini</name><name sortKey="Bade, Aditya N" sort="Bade, Aditya N" uniqKey="Bade A" first="Aditya N." last="Bade">Aditya N. Bade</name><name sortKey="Banoub, Mary" sort="Banoub, Mary" uniqKey="Banoub M" first="Mary" last="Banoub">Mary Banoub</name><name sortKey="Bella, Ramona" sort="Bella, Ramona" uniqKey="Bella R" first="Ramona" last="Bella">Ramona Bella</name><name sortKey="Burdo, Tricia H" sort="Burdo, Tricia H" uniqKey="Burdo T" first="Tricia H." last="Burdo">Tricia H. Burdo</name><name sortKey="Chen, Chen" sort="Chen, Chen" uniqKey="Chen C" first="Chen" last="Chen">Chen Chen</name><name sortKey="Donadoni, Martina" sort="Donadoni, Martina" uniqKey="Donadoni M" first="Martina" last="Donadoni">Martina Donadoni</name><name sortKey="Edagwa, Benson" sort="Edagwa, Benson" uniqKey="Edagwa B" first="Benson" last="Edagwa">Benson Edagwa</name><name sortKey="Elango, Monalisha" sort="Elango, Monalisha" uniqKey="Elango M" first="Monalisha" last="Elango">Monalisha Elango</name><name sortKey="Ferrante, Pasquale" sort="Ferrante, Pasquale" uniqKey="Ferrante P" first="Pasquale" last="Ferrante">Pasquale Ferrante</name><name sortKey="Gautam, Nagsen" sort="Gautam, Nagsen" uniqKey="Gautam N" first="Nagsen" last="Gautam">Nagsen Gautam</name><name sortKey="Gendelman, Howard E" sort="Gendelman, Howard E" uniqKey="Gendelman H" first="Howard E." last="Gendelman">Howard E. Gendelman</name><name sortKey="Gorantla, Santhi" sort="Gorantla, Santhi" uniqKey="Gorantla S" first="Santhi" last="Gorantla">Santhi Gorantla</name><name sortKey="Gordon, Jennifer" sort="Gordon, Jennifer" uniqKey="Gordon J" first="Jennifer" last="Gordon">Jennifer Gordon</name><name sortKey="Hilaire, James R" sort="Hilaire, James R" uniqKey="Hilaire J" first="James R." last="Hilaire">James R. Hilaire</name><name sortKey="Jacobson, Jeffrey M" sort="Jacobson, Jeffrey M" uniqKey="Jacobson J" first="Jeffrey M." last="Jacobson">Jeffrey M. Jacobson</name><name sortKey="Kaminski, Rafal" sort="Kaminski, Rafal" uniqKey="Kaminski R" first="Rafal" last="Kaminski">Rafal Kaminski</name><name sortKey="Khalili, Kamel" sort="Khalili, Kamel" uniqKey="Khalili K" first="Kamel" last="Khalili">Kamel Khalili</name><name sortKey="Lin, Zhiyi" sort="Lin, Zhiyi" uniqKey="Lin Z" first="Zhiyi" last="Lin">Zhiyi Lin</name><name sortKey="Mancuso, Pietro" sort="Mancuso, Pietro" uniqKey="Mancuso P" first="Pietro" last="Mancuso">Pietro Mancuso</name><name sortKey="Mathews, Saumi" sort="Mathews, Saumi" uniqKey="Mathews S" first="Saumi" last="Mathews">Saumi Mathews</name><name sortKey="Mcmillan, Joellyn" sort="Mcmillan, Joellyn" uniqKey="Mcmillan J" first="Joellyn" last="Mcmillan">Joellyn Mcmillan</name><name sortKey="Mosley, R Lee" sort="Mosley, R Lee" uniqKey="Mosley R" first="R. Lee" last="Mosley">R. Lee Mosley</name><name sortKey="Poluektova, Larisa Y" sort="Poluektova, Larisa Y" uniqKey="Poluektova L" first="Larisa Y." last="Poluektova">Larisa Y. Poluektova</name><name sortKey="Robinson, Jake A" sort="Robinson, Jake A" uniqKey="Robinson J" first="Jake A." last="Robinson">Jake A. Robinson</name><name sortKey="Sariyer, Ilker K" sort="Sariyer, Ilker K" uniqKey="Sariyer I" first="Ilker K." last="Sariyer">Ilker K. Sariyer</name><name sortKey="Sariyer, Rahsan" sort="Sariyer, Rahsan" uniqKey="Sariyer R" first="Rahsan" last="Sariyer">Rahsan Sariyer</name><name sortKey="Sillman, Brady" sort="Sillman, Brady" uniqKey="Sillman B" first="Brady" last="Sillman">Brady Sillman</name><name sortKey="Su, Hang" sort="Su, Hang" uniqKey="Su H" first="Hang" last="Su">Hang Su</name><name sortKey="Young, Won Bin" sort="Young, Won Bin" uniqKey="Young W" first="Won-Bin" last="Young">Won-Bin Young</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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