title: Genistein interferes with SDF-1- and HIV-mediated actin dynamics and inhibits HIV infection of resting CD4 T cells.
abstract: 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.
authors.affiliation: National Center for Biodefense and Infectious Diseases, Department of Molecular and Microbiology, George Mason University, Manassas VA 20110, USA. ywu8@gmu.edu.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.forename: Xuehua
authors.initials: X
authors.lastname: Xu
authors.forename: Taban K
authors.initials: TK
authors.lastname: Rasheed
authors.forename: Alyson
authors.initials: A
authors.lastname: Yoder
authors.forename: Dongyang
authors.initials: D
authors.lastname: Yu
authors.forename: Huizhi
authors.initials: H
authors.lastname: Liang
authors.forename: Fei
authors.initials: F
authors.lastname: Yi
authors.forename: Todd
authors.initials: T
authors.lastname: Hawley
authors.forename: Tian
authors.initials: T
authors.lastname: Jin
authors.forename: Binhua
authors.initials: B
authors.lastname: Ling
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors*; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors*; D019833:Genistein / Q000378:metabolism*; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008253:Macaca mulatta; D015398:Signal Transduction / Q000187:drug effects; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000502:physiology; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000199:Actins; D000998:Antiviral Agents; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019833:Genistein