title: A V3 loop-dependent gp120 element disrupted by CD4 binding stabilizes the human immunodeficiency virus envelope glycoprotein trimer.
abstract: Human immunodeficiency virus (HIV-1) entry into cells is mediated by a trimeric complex consisting of noncovalently associated gp120 (exterior) and gp41 (transmembrane) envelope glycoproteins. The binding of gp120 to receptors on the target cell alters the gp120-gp41 relationship and activates the membrane-fusing capacity of gp41. Interaction of gp120 with the primary receptor, CD4, results in the exposure of the gp120 third variable (V3) loop, which contributes to binding the CCR5 or CXCR4 chemokine receptors. We show here that insertions in the V3 stem or polar substitutions in a conserved hydrophobic patch near the V3 tip result in decreased gp120-gp41 association (in the unliganded state) and decreased chemokine receptor binding (in the CD4-bound state). Subunit association and syncytium-forming ability of the envelope glycoproteins from primary HIV-1 isolates were disrupted more by V3 changes than those of laboratory-adapted HIV-1 envelope glycoproteins. Changes in the gp120 beta2, beta19, beta20, and beta21 strands, which evidence suggests are proximal to the V3 loop in unliganded gp120, also resulted in decreased gp120-gp41 association. Thus, a gp120 element composed of the V3 loop and adjacent beta strands contributes to quaternary interactions that stabilize the unliganded trimer. CD4 binding dismantles this element, altering the gp120-gp41 relationship and rendering the hydrophobic patch in the V3 tip available for chemokine receptor binding.
authors.affiliation: Dana-Farber Cancer Institute, 44 Binney Street, CLS 1010, Boston, MA 02115, USA.
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Xiang
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pacheco
authors.forename: Kevin
authors.initials: K
authors.lastname: Alexander
authors.forename: Wen
authors.initials: W
authors.lastname: Yuan
authors.forename: Carlo
authors.initials: C
authors.lastname: Rizzuto
authors.forename: Chih-Chin
authors.initials: CC
authors.lastname: Huang
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
mesh_terms: D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000378:metabolism*; D000939:Epitopes; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology / Q000502:physiology; D015700:HIV Envelope Protein gp41 / Q000737:chemistry; D008969:Molecular Sequence Data; D011487:Protein Conformation; D021122:Protein Subunits; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D015704:CD4 Antigens; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D021122:Protein Subunits; D019713:Receptors, CCR5; C514793:gp120 protein, Human immunodeficiency virus 1