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Targeting ABL1 or ARG Tyrosine Kinases to Restrict HIV-1 Infection in Primary CD4+ T-Cells or in Humanized NSG Mice.
- Source :
-
Journal of acquired immune deficiency syndromes (1999) [J Acquir Immune Defic Syndr] 2019 Dec 01; Vol. 82 (4), pp. 407-415. - Publication Year :
- 2019
-
Abstract
- Background: Previous studies support dasatinib as a potent inhibitor of HIV-1 replication. However, a functional distinction between 2 kinase targets of the drug, ABL1 and ARG, has not been assessed.<br />Setting: We used primary CD4 T-cells, CD8-depleted peripheral blood mononuclear cells (PBMCs) from a treatment naïve HIV-1 patient, and a humanized mouse model of HIV-1 infection. We assessed the roles of ABL1 and ARG during HIV-1 infection and use of dasatinib as a potential antiviral against HIV-1 in humanized mice.<br />Methods: Primary CD4 T-cells were administered siRNA targeting ABL1 or ARG, then infected with HIV-1 containing luciferase reporter viruses. Quantitative polymerase chain reaction of viral integration of 4 HIV-1 strains was also assessed. CD8-depleted PBMCs were treated for 3 weeks with dasatinib. NSG mice were engrafted with CD34 pluripotent stem cells from human fetal cord blood, and infected with Ba-L virus after 19 weeks. Mice were treated daily with dasatinib starting 5 weeks after infection.<br />Results: siRNA knockdown of ABL1 or ARG had no effect on viral reverse transcripts, but increased 2-LTR circles 2- to 4-fold and reduced viral integration 2- to 12-fold. siRNA knockdown of ARG increased SAMHD1 activation, whereas knockdown of either kinase reduced RNA polymerase II activation. Treating CD8-depleted PBMCs from a treatment-naïve patient with 50 nM of dasatinib for 3 weeks reduced p24 levels by 99.8%. Ba-L (R5)-infected mice injected daily with dasatinib showed a 95.1% reduction in plasma viral load after 2 weeks of treatment.<br />Conclusions: We demonstrate a novel nuclear role for ABL1 and ARG in ex vivo infection experiments, and proof-of-principle use of dasatinib in a humanized mouse model of HIV-1 infection.
- Subjects :
- Animals
CD4-Positive T-Lymphocytes immunology
Dasatinib therapeutic use
Female
HIV Infections immunology
Humans
Male
Mice
Mice, Inbred NOD
Protein-Tyrosine Kinases physiology
Proto-Oncogene Proteins c-abl physiology
RNA, Small Interfering genetics
HIV Infections drug therapy
HIV-1 drug effects
Protein Kinase Inhibitors therapeutic use
Protein-Tyrosine Kinases antagonists & inhibitors
Proto-Oncogene Proteins c-abl antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1944-7884
- Volume :
- 82
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of acquired immune deficiency syndromes (1999)
- Publication Type :
- Academic Journal
- Accession number :
- 31658184
- Full Text :
- https://doi.org/10.1097/QAI.0000000000002144