Role of Abl Kinase and the Wave2 Signaling Complex in HIV-1 Entry at a Post-Hemifusion Step

• DOI: 10.1371/journal.ppat.1000956
• Publication Date: 2010-06-17T20:40:01Z
• Authors: Brooke Harmon; Nancy Campbell; Lee Ratner
• Keywords: Rac GTP-Binding Proteins; Cell fusion

Entry of human immunodeficiency virus type 1 (HIV-1) commences with binding the envelope glycoprotein (Env) to receptor CD4, and one two coreceptors, CXCR4 or CCR5. Env-mediated signaling through coreceptor results in Galphaq-mediated Rac activation actin cytoskeleton rearrangements necessary for fusion. Guanine nucleotide exchange factors (GEFs) activate regulate its downstream protein effectors. In this study we show that Env-induced is mediated by GEF Tiam-1, which associates adaptor IRSp53 link Wave2 complex. tyrosine kinase Abl then complex promote Arp2/3-dependent polymerization. cell-cell fusion, virus-cell fusion HIV-1 infection are dependent on Abl, IRSp53, Wave2, Arp3 as shown attenuation cells expressing siRNA targeted these components. Env-dependent were also inhibited inhibitors, imatinib, nilotinib, dasatinib. Treatment inhibitors did not affect cell viability surface expression CD4 Similar siRNAs obtained when was measured, lines primary target. Using membrane curving agents fluorescence microscopy, showed inhibition activity arrests at hemifusion (lipid mixing) step, suggesting a role Abl-mediated remodeling pore formation expansion. These suggest potential utility treat infected patients.