title: The external domains of the HIV-1 envelope are a mutational cold spot.
abstract: In RNA viruses, mutations occur fast and have large fitness effects. While this affords remarkable adaptability, it can also endanger viral survival due to the accumulation of deleterious mutations. How RNA viruses reconcile these two opposed facets of mutation is still unknown. Here we show that, in human immunodeficiency virus (HIV-1), spontaneous mutations are not randomly located along the viral genome. We find that the viral mutation rate experiences a threefold reduction in the region encoding the most external domains of the viral envelope, which are strongly targeted by neutralizing antibodies. This contrasts with the hypermutation mechanisms deployed by other, more slowly mutating pathogens such as DNA viruses and bacteria, in response to immune pressure. We show that downregulation of the mutation rate in HIV-1 is exerted by the template RNA through changes in sequence context and secondary structure, which control the activity of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (A3)-mediated cytidine deamination and the fidelity of the viral reverse transcriptase.
authors.affiliation: Instituto Cavanilles de Biodiversidad y Biología Evolutiva, Universitat de València, C/ Catedrático José Beltrán 2, Paterna, 46980 Valencia, Spain.
authors.forename: Ron
authors.identifier: http://orcid.org/0000-0002-7612-4611
authors.initials: R
authors.lastname: Geller
authors.affiliation: Instituto Cavanilles de Biodiversidad y Biología Evolutiva, Universitat de València, C/ Catedrático José Beltrán 2, Paterna, 46980 Valencia, Spain.|Architecture et Réactivité de l'ARN, Université de Strasbourg, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg-CNRS, 15 rue René Descartes, 67084 Strasbourg, France.
authors.forename: Pilar
authors.initials: P
authors.lastname: Domingo-Calap
authors.affiliation: Instituto Cavanilles de Biodiversidad y Biología Evolutiva, Universitat de València, C/ Catedrático José Beltrán 2, Paterna, 46980 Valencia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Cuevas
authors.affiliation: Architecture et Réactivité de l'ARN, Université de Strasbourg, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg-CNRS, 15 rue René Descartes, 67084 Strasbourg, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Rossolillo
authors.affiliation: Architecture et Réactivité de l'ARN, Université de Strasbourg, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg-CNRS, 15 rue René Descartes, 67084 Strasbourg, France.
authors.forename: Matteo
authors.initials: M
authors.lastname: Negroni
authors.affiliation: Instituto Cavanilles de Biodiversidad y Biología Evolutiva, Universitat de València, C/ Catedrático José Beltrán 2, Paterna, 46980 Valencia, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Sanjuán
mesh_terms: D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D059645:Mutation Rate; D017434:Protein Structure, Tertiary; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D014759:Viral Envelope Proteins