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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Gartenhaus, Ronald B. Medina-moreno, Sandra Zapata, Juan C. Heredia, Alonso Davis, Charles Sausville, Edward Gallo, Robert C. Redfield, Robert R. Le, Nhut |
| Description | Author Affiliation: Heredia A ( Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201); Le N ( Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201); Gartenhaus RB ( Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201.); Sausville E ( Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201.); Medina-Moreno S ( Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201); Zapata JC ( Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201); Davis C ( Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201); Gallo RC ( Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201); Redfield RR ( Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201); |
| Abstract | HIV necessitates host factors for successful completion of its life cycle. Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric inhibitor of mTOR that selectively inhibits mTORC1. Rapamycin interferes with viral entry of CCR5 (R5)-tropic HIV and with basal transcription of the HIV LTR, potently inhibiting replication of R5 HIV but not CXCR4 (X4)-tropic HIV in primary cells. The recently developed ATP-competitive mTOR kinase inhibitors (TOR-KIs) inhibit both mTORC1 and mTORC2. Using INK128 as a prototype TOR-KI, we demonstrate potent inhibition of both R5 and X4 HIV in primary lymphocytes (EC50 < 50 nM), in the absence of toxicity. INK128 inhibited R5 HIV entry by reducing CCR5 levels. INK128 also inhibited both basal and induced transcription of HIV genes, consistent with inhibition of mTORC2, whose activity is critical for phosphorylation of PKC isoforms and, in turn, induction of NF-κB. INK128 enhanced the antiviral potency of the CCR5 antagonist maraviroc, and had favorable antiviral interactions with HIV inhibitors of reverse transcriptase, integrase and protease. In humanized mice, INK128 decreased plasma HIV RNA by >2 log10 units and partially restored CD4/CD8 cell ratios. Targeting of cellular mTOR with INK128 (and perhaps others TOR-KIs) provides a potential strategy to inhibit HIV, especially in patients with drug resistant HIV strains. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 30 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | HIV Infections Metabolism HIV-1 Physiology TOR Serine-Threonine Kinases Adenosine Triphosphate Chemistry Allosteric Site Animals Anti-HIV Agents Therapeutic Use Benzoxazoles CD4-Positive T-Lymphocytes Cytology Catalytic Domain Cell Proliferation Cell Survival Disease Models, Animal Dose-Response Relationship, Drug Gene Expression Regulation Interleukin-2 Leukocytes, Mononuclear Lymphocytes Virology Mice NF-kappa B Pyrimidines Transcription, Genetic Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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