Functional interaction between the cytoplasmic leucine-zipper domain of HIV-1 gp41 and p115-RhoGEF

The long cytoplasmic tail of the human immunodeficiency virus (HIV)-1 trans membrane protein gp41 (gp41C) is implicated in the replication and cytopath icity of HIV-1 [1]. Little is known about the specific functions of gp41C, however. HIV-1 or simian immunodeficiency virus (SIV) mutants with defectiv e gp41C have cell-type- or species-dependent phenotypes [2-6], Thus, host f actors are implicated in mediating the functions of gp41C. We report here t hat gp41C interacted with the carboxy-terminal regulatory domain of p115-Rh oGEF [7], a specific guanine nucleotide exchange factor (GEF) and activator of the RhoA GTPase, which regulates actin stress fiber formation, activati on of serum response factor (SRF) and cell proliferation [8,9]. We demonstr ate that gp41C inhibited p115-mediated actin stress fiber formation and act ivation of SRF. An amphipathic helix region with a leucine-zipper motif in gp41C is involved in its interaction with p115. Mutations in gp41C leading to loss of interaction with p115 impaired HIV-1 replication in human T cell s. These findings suggest that an important function of gp41C is to modulat e the activity of p115-RhoGEF and they thus reveal a new potential anti-HIV -1 target. (C) 1999 Elsevier Science Ltd. All rights reserved.