title: Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies.
abstract: HIV-1 envelope glycoprotein gp41 undergoes large conformational changes to drive fusion of viral and target cell membranes, adopting at least three distinct conformations during the viral entry process. Neutralizing antibodies against gp41 block HIV-1 infection by targeting gp41's membrane-proximal external region in a fusion-intermediate state. Here we report biochemical and structural evidence that non-neutralizing antibodies, capable of binding with high affinity to an immunodominant segment adjacent to the neutralizing epitopes in the membrane-proximal region, recognize a gp41 conformation that exists only when membrane fusion is complete. We propose that these non-neutralizing antibodies are induced in HIV-1-infected individuals by gp41 in a triggered, postfusion form and contribute to production of ineffective humoral responses. These results have important implications for gp41-based vaccine design.
authors.affiliation: Division of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Frey
authors.forename: Jia
authors.initials: J
authors.lastname: Chen
authors.forename: Sophia
authors.initials: S
authors.lastname: Rits-Volloch
authors.forename: Michael M
authors.initials: MM
authors.lastname: Freeman
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000502:physiology; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology; D000914:Antibodies, Viral / Q000737:chemistry* / Q000276:immunology; D018360:Crystallography, X-Ray; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000502:physiology; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D053586:Virus Internalization
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D015700:HIV Envelope Protein gp41; D007140:Immunoglobulin Fab Fragments; C514787:gp41 protein, Human immunodeficiency virus 1