title: Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors.
abstract: Interactions between the gp120 and gp41 subunits of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer maintain the metastable unliganded form of the viral spike. Binding of gp120 to the receptor, CD4, changes the Env conformation to promote gp120 interaction with the second receptor, CCR5 or CXCR4. CD4 binding also induces the transformation of Env into the prehairpin intermediate, in which the gp41 heptad repeat 1 (HR1) coiled coil is assembled at the trimer axis. In nature, HIV-1 Envs must balance the requirements to maintain the noncovalent association of gp120 with gp41 and to evade the host antibody response with the need to respond to CD4 binding. Here we show that the gp41 HR1 region contributes to gp120 association with the unliganded Env trimer. Changes in particular amino acid residues in the gp41 HR1 region decreased the efficiency with which Env moved from the unliganded state. Thus, these gp41 changes decreased the sensitivity of HIV-1 to cold inactivation and ligands that require Env conformational changes to bind efficiently. Conversely, these gp41 changes increased HIV-1 sensitivity to small-molecule entry inhibitors that block Env conformational changes induced by CD4. Changes in particular gp41 HR1 amino acid residues can apparently affect the relative stability of the unliganded state and CD4-induced conformations. Thus, the gp41 HR1 region contributes to the association with gp120 and regulates Env transitions from the unliganded state to downstream conformations.IMPORTANCEThe development of an efficient vaccine able to prevent HIV infection is a worldwide priority. Knowledge of the envelope glycoprotein structure and the conformational changes that occur after receptor engagement will help researchers to develop an immunogen able to elicit antibodies that block HIV-1 transmission. Here we identify residues in the HIV-1 transmembrane envelope glycoprotein that stabilize the unliganded state by modulating the transitions from the unliganded state to the CD4-bound state.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.|Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pacheco
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.|Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Nirmin
authors.initials: N
authors.lastname: Alsahafi
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.|Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Olfa
authors.initials: O
authors.lastname: Debbeche
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.|Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Prévost
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.|Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Shilei
authors.initials: S
authors.lastname: Ding
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.|Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Chapleau
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Alon
authors.initials: A
authors.lastname: Herschhorn
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Princiotto
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Bruno
authors.initials: B
authors.lastname: Melillo
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Youdong
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA joseph_sodroski@dfci.harvard.edu andres.finzi@umontreal.ca.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada joseph_sodroski@dfci.harvard.edu andres.finzi@umontreal.ca.|Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.|Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000737:chemistry*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; C451732:BMS 806; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D010879:Piperazines; C514793:gp120 protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1
keywords: HIV-1; HR1; antibody resistance; gp120; gp41; intrinsic envelope reactivity; soluble CD4