The tyrosine kinase inhibitor genistein blocks HIV-1 infection in primary human macrophages.
Binding of HIV-1 envelope glycoprotein (Env) to its cellular receptors elicits a variety of signaling events, including the activation of select tyrosine kinases. To evaluate the potential role of such signaling, we examined the effects of the tyrosine kinase inhibitor, genistein, on HIV-1 entry and infection of human macrophages using a variety of assays. Without altering cell viability, cell surface expression of CD4 and CCR5 or their abilities to interact with Env, genistein inhibited infection of macrophages by reporter gene-encoding, beta-lactamase containing, or wild type virions, as well as Env-mediated cell-fusion. The observation that genistein blocked virus infection if applied before, during or immediately after the infection period, but not 24h later; coupled with a more pronounced inhibition of infection in the reporter gene assays as compared to both beta-lactamase and p24 particle entry assays, imply that genistein exerts its inhibitory effects on both entry and early post-entry steps. These findings suggest that other exploitable targets, or steps, of the HIV-1 infection process may exist and could serve as additional opportunities for the development of new therapeutics.
Stantchev
Tzanko S
TS
Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed Services University Bethesda, 4301 Jones Bridge Road, MD 20814, USA.
Markovic
Ingrid
I
Telford
William G
WG
Clouse
Kathleen A
KA
Broder
Christopher C
CC
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000187:drug effects / Q000378:metabolism; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000821:virology; D008561:Membrane Fusion / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D015699:HIV Envelope Protein gp120; D014409:Tumor Necrosis Factor-alpha; D019833:Genistein; D011505:Protein-Tyrosine Kinases