Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-10366-y
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Funding
- ViiV Healthcare
- University of Nebraska Foundation
- M.D. Emerging Neuroscience Research Laboratory
- Margaret R. Larson Professorship
- Frances and Louie Blumkin Endowment
- Harriet Singer Endowment
- National Institute of Health
- University of Nebraska Medical Center [R01MH104147, R01NS36126, R01NS034239, P01NS43985, P30MH062261, P30AI078498, R01AG043540, P30MH092177, P01DA028555, P01DA037830, R01MH110360, R01DA013137, R01NS087971, R24OD018546, R01DA42706]
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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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