title: Molecular determinants of acute single-cell lysis by human immunodeficiency virus type 1.
abstract: Human immunodeficiency virus type 1 (HIV-1) infection of CD4-positive lymphocytes is accompanied by acute cytopathic effects, i.e., syncytium formation and single-cell lysis. Syncytium formation involves cell-cell fusion mediated by viral envelope glycoproteins on the surface of infected cells and by CD4 glycoproteins on adjacent cells. The molecular basis for the lysis of single-HIV-1 infected cells is unclear. Here we report that the expression of functional envelope glycoproteins from primary and laboratory-adapted HIV-1 isolates resulted in the lysis of single CD4-positive lymphocytes. As was previously observed in HIV-1 infected cultures, single-cell lysis in this system primarily involved necrosis and was not inhibited by soluble CD4. Binding of the viral envelope glycoproteins to the CD4 glycoprotein facilitated, but was not sufficient for, cytolysis. Importantly, the ability of the HIV-1 envelope glycoproteins to mediate membrane fusion was essential for single-cell killing. By contrast, the long cytoplasmic tail of the gp41 transmembrane envelope glycoprotein was neither necessary nor sufficient for single-cell lysis. These results suggest that intracellular envelope glycoprotein-CD4 interactions initiate autofusion events that disrupt cell membrane integrity, leading to single-cell lysis by HIV-1.
authors.affiliation: Division of Human Retrovirology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cao
authors.forename: I W
authors.initials: IW
authors.lastname: Park
authors.forename: A
authors.initials: A
authors.lastname: Cooper
authors.forename: J
authors.initials: J
authors.lastname: Sodroski
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000648:ultrastructure / Q000821:virology*; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral; D015870:Gene Expression; D015686:Gene Products, env / Q000235:genetics / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000502:physiology; D019302:HIV Envelope Protein gp160; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000502:physiology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D009154:Mutation; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology; D014162:Transfection
chemical_list: D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D015700:HIV Envelope Protein gp41; D008562:Membrane Glycoproteins; D011498:Protein Precursors