| Autor: |
Dash, Prasanta K., Chen Chen, Kaminski, Rafal, Hang Su, Mancuso, Pietro, Sillman, Brady, Chen Zhang, Shuren Liao, Sravanam, Sruthi, Hong Liu, Waight, Emiko, Lili Guo, Mathews, Saumi, Sariyer, Rahsan, Mosley, R. Lee, Poluektova, Larisa Y., Caocci, Maurizio, Amini, Shohreh, Gorantla, Santhi, Burdo, Tricia H. |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 5/9/2023, Vol. 120 Issue 19, p1-10, 35p |
| Abstrakt: |
Treatment of HIV-1ADA-infected CD34+ NSG-humanized mice with long-acting ester prodrugs of cabotegravir, lamivudine, and abacavir in combination with native rilpivirine was followed by dual CRISPR-Cas9 C-C chemokine receptor type five (CCR5) and HIV-1 proviral DNA gene editing. This led to sequential viral suppression, restoration of absolute human CD4+ T cell numbers, then elimination of replication-competent virus in 58% of infected mice. Dual CRISPR therapies enabled the excision of integrated proviral DNA in infected human cells contained within live infected animals. Highly sensitive nucleic acid nested and droplet digital PCR, RNAscope, and viral outgrowth assays affirmed viral elimination. HIV-1 was not detected in the blood, spleen, lung, kidney, liver, gut, bone marrow, and brain of virus-free animals. Progeny virus from adoptively transferred and CRISPR-treated virus-free mice was neither detected nor recovered. Residual HIV-1 DNA fragments were easily seen in untreated and viral-rebounded animals. No evidence of off-target toxicities was recorded in any of the treated animals. Importantly, the dual CRISPR therapy demonstrated statistically significant improvements in HIV-1 cure percentages compared to single treatments. Taken together, these observations underscore a pivotal role of combinatorial CRISPR gene editing in achieving the elimination of HIV-1 infection. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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