Genistein interferes with SDF-1- and HIV-mediated actin dynamics and inhibits HIV infection of resting CD4 T cells
| Autor: | Dongyang Yu, Jia Guo, Taban K. Rasheed, Xuehua Xu, Yuntao Wu, Alyson Yoder, Tian Jin, Binhua Ling, Todd Hawley, Fei Yi, Huizhi Liang |
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| Rok vydání: | 2013 |
| Předmět: |
CD4-Positive T-Lymphocytes
Chemokine medicine.drug_class Simian Acquired Immunodeficiency Syndrome Genistein Biology Pharmacology CXCR4 Antiviral Agents CCL5 Tyrosine-kinase inhibitor SDF-1 03 medical and health sciences chemistry.chemical_compound Virology medicine Sunitinib Animals Humans Cells Cultured Actin 030304 developmental biology 0303 health sciences Research 030302 biochemistry & molecular biology virus diseases HIV Chemotaxis Cofilin Virus Internalization Molecular biology Macaca mulatta Actins Chemokine CXCL12 3. Good health CD4 Lymphocyte Count Infectious Diseases LIMK1 chemistry biology.protein HIV-1 Simian Immunodeficiency Virus Tyrosine kinase Signal Transduction |
| Zdroj: | Retrovirology |
| ISSN: | 1742-4690 |
| Popis: | Background Binding of HIV to the chemokine coreceptor CXCR4 mediates viral fusion and signal transduction that promotes actin dynamics critical for HIV infection of blood resting CD4 T cells. It has been suggested that this gp120-mediated actin activity resembles the chemotactic actin dynamics mediated by chemokines such as SDF-1. To determine whether inhibiting SDF-1-mediated chemotactic activity can also inhibit HIV infection, we screened several inhibitors known to reduce SDF-1-mediated chemotaxis of T cells. Results We found that a tyrosine kinase inhibitor, genistein, inhibited both SDF-1-mediated chemotaxis and HIV infection of resting CD4 T cells. Genistein was also found to interfere with SDF-1- and HIV-mediated actin dynamics in CD4 T cells. This reduction in actin activity correlates with genistein-mediated inhibition of viral DNA accumulation in resting CD4 T cells. In addition, we also tested two other tyrosine kinase inhibitors, sunitinib and AG1478. Sunitinib, but not AG1478, inhibited HIV infection of resting CD4 T cells. We further tested the safety of genistein in 3 Chinese rhesus macaques (Macaca mulatta), and each animal was given a monotherapy of genistein at 10 mg/kg orally for 12 weeks. No adverse drug effects were observed in these animals. Conclusions Our results suggest that novel therapeutic strategies can be developed based on targeting cellular proteins involved in HIV-dependent signaling. This approach can interfere with HIV-mediated actin dynamics and inhibit HIV infection. |
| Databáze: | OpenAIRE |
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