title: Buffering deleterious polymorphisms in highly constrained parts of HIV-1 envelope by flexible regions.
abstract: Covariation is an essential process that leads to coevolution of parts of proteins and genomes. In organisms subject to strong selective pressure, coevolution is central to keep the balance between the opposite requirements of antigenic variation and retention of functionality. Being the viral component most exposed to the external environment, the HIV-1 glycoprotein gp120 constitutes the main target of the immune response. Accordingly its more external portions are characterised by extensive sequence heterogeneity fostering constant antigenic variation.
  
  
  
  We report that a single polymorphism, present at the level of the viral population in the conserved internal region C2, was sufficient to totally abolish Env functionality when introduced in an exogenous genetic context. The prominent defect of the non-functional protein is a block occurring after recognition of the co-receptor CCR5, likely due to an interference with the subsequent conformational changes that lead to membrane fusion. We also report that the presence of compensatory polymorphisms at the level of the external and hypervariable region V3 fully restored the functionality of the protein. The functional revertant presents different antigenic profiles and sensitivity to the entry inhibitor TAK 779.
  
  
  
  Our data suggest that variable regions, besides harbouring intrinsic extensive antigenic diversity, can also contribute to sequence diversification in more structurally constrained parts of the gp120 by buffering the deleterious effect of polymorphisms, further increasing the genetic flexibility of the protein and the antigenic repertoire of the viral population.
authors.affiliation: Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 15 rue René Descartes, 67084, Strasbourg, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Gasser
authors.affiliation: Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 15 rue René Descartes, 67084, Strasbourg, France.|U1016, UMR 8104, INSERM-CNRS, Institut Cochin, Université Paris Descartes, Paris, France.
authors.forename: Meriem
authors.initials: M
authors.lastname: Hamoudi
authors.affiliation: Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 15 rue René Descartes, 67084, Strasbourg, France.
authors.forename: Martina
authors.initials: M
authors.lastname: Pellicciotta
authors.affiliation: INSERM U1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, Paris, France.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: INSERM U966, Université François Rabelais, Tours, France.
authors.forename: Clara
authors.initials: C
authors.lastname: Visdeloup
authors.affiliation: INSERM U1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Colin
authors.affiliation: INSERM U966, Université François Rabelais, Tours, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Braibant
authors.affiliation: INSERM U1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lagane
authors.affiliation: Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 15 rue René Descartes, 67084, Strasbourg, France. m.negroni@ibmc-cnrs.unistra.fr.
authors.forename: Matteo
authors.initials: M
authors.lastname: Negroni
mesh_terms: D000577:Amides / Q000494:pharmacology; D000940:Antigenic Variation; D015704:CD4 Antigens / Q000378:metabolism; D019143:Evolution, Molecular; D014644:Genetic Variation; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D006801:Humans; D011110:Polymorphism, Genetic; D055550:Protein Stability; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000378:metabolism; D016415:Sequence Alignment; D053586:Virus Internalization
chemical_list: D000577:Amides; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; C119369:TAK 779
keywords: Antigenic variation; Coevolution; Envelope; HIV; Viral entry