title: Regulation of human immunodeficiency virus type 1 Env-mediated membrane fusion by viral protease activity.
abstract: We and others have presented evidence for a direct interaction between the matrix (MA) domain of the human immunodeficiency virus type 1 (HIV-1) Gag protein and the cytoplasmic tail of the transmembrane envelope (Env) glycoprotein gp41. In addition, it has been postulated that the MA domain of Gag undergoes a conformational change following Gag processing, and the cytoplasmic tail of gp41 has been shown to modulate Env-mediated membrane fusion activity. Together, these results raise the possibility that the interaction between the gp41 cytoplasmic tail and MA is regulated by protease (PR)-mediated Gag processing, perhaps affecting Env function. To examine whether Gag processing affects Env-mediated fusion, we compared the ability of wild-type (WT) HIV-1 Env and a mutant lacking the gp41 cytoplasmic tail to induce fusion in the context of an active (PR(+)) or inactive (PR(-)) viral PR. We observed that PR(-) virions bearing WT Env displayed defects in cell-cell fusion. Impaired fusion did not appear to be due to differences in the levels of virion-associated Env, in CD4-dependent binding to target cells, or in the formation of the CD4-induced gp41 six-helix bundle. Interestingly, truncation of the gp41 cytoplasmic tail reversed the fusion defect. These results suggest that interactions between unprocessed Gag and the gp41 cytoplasmic tail suppress fusion.
authors.affiliation: Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan. tmura@med.u-ryukyu.ac.jp
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Murakami
authors.forename: Sherimay
authors.initials: S
authors.lastname: Ablan
authors.forename: Eric O
authors.initials: EO
authors.lastname: Freed
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D002459:Cell Fusion; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D015686:Gene Products, env / Q000378:metabolism*; D015683:Gene Products, gag / Q000737:chemistry / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism; D016333:HIV Protease / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D019169:Jurkat Cells; D008561:Membrane Fusion / Q000187:drug effects*; D014771:Virion / Q000378:metabolism
chemical_list: D015686:Gene Products, env; D015683:Gene Products, gag; D015700:HIV Envelope Protein gp41; D016333:HIV Protease