Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication
| Autor: | Campbell, Grant R, Bruckman, Rachel S, Herns, Shayna D, Joshi, Shweta, Durden, Donald L, Spector, Stephen A |
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| Rok vydání: | 2018 |
| Předmět: |
autophagy
Biochemistry & Molecular Biology Anti-HIV Agents Cells JQ1 HIV Infections Cell Cycle Proteins macrophage SF2523 Virus Replication Medical and Health Sciences Humans Protein Kinase Inhibitors Phosphoinositide-3 Kinase Inhibitors Cultured human immunodeficiency virus Macrophages TOR Serine-Threonine Kinases Imidazoles Nuclear Proteins Azepines Triazoles Biological Sciences NVP-BEZ235 Infectious Diseases 5.1 Pharmaceuticals 6.1 Pharmaceuticals Chemical Sciences HIV-1 Quinolines HIV/AIDS autophagy-related protein 7 phosphatidylinositol signaling Phosphatidylinositol 3-Kinase Infection Transcription Factors Signal Transduction |
| Zdroj: | The Journal of biological chemistry, vol 293, iss 16 |
| Popis: | In this study, we investigated the effects of the dual phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/MTOR) inhibitor dactolisib (NVP-BEZ235), the PI3K/MTOR/bromodomain-containing protein 4 (BRD4) inhibitor SF2523, and the bromodomain and extra terminal domain inhibitor JQ1 on the productive infection of primary macrophages with human immunodeficiency type-1 (HIV). These inhibitors did not alter the initial susceptibility of macrophages to HIV infection. However, dactolisib, JQ1, and SF2523 all decreased HIV replication in macrophages in a dose-dependent manner via degradation of intracellular HIV through autophagy. Macrophages treated with dactolisib, JQ1, or SF2523 displayed an increase in LC3B lipidation combined with SQSTM1 degradation without inducing increased cell death. LC3B-II levels were further increased in the presence of pepstatin A suggesting that these inhibitors induce autophagic flux. RNA interference for ATG5 and ATG7 and pharmacological inhibitors of autophagosome-lysosome fusion and of lysosomal hydrolases all blocked the inhibition of HIV. Thus, we demonstrate that the mechanism of PI3K/MTOR and PI3K/MTOR/BRD4 inhibitor suppression of HIV requires the formation of autophagosomes, as well as their subsequent maturation into autolysosomes. These data provide further evidence in support of a role for autophagy in the control of HIV infection and open new avenues for the use of this class of drugs in HIV therapy. |
| Databáze: | OpenAIRE |
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