title: Structural domains within the HIV-1 mRNA and the ribosomal protein S25 influence cap-independent translation initiation.
abstract: The 5' leader of the HIV-1 genomic RNA is a multifunctional region that folds into secondary/tertiary structures that regulate multiple processes during viral replication including translation initiation. In this work, we examine the internal ribosome entry site (IRES) located in the 5' leader that drives translation initiation of the viral Gag protein under conditions that hinder cap-dependent translation initiation. We show that activity of the HIV-1 IRES relies on ribosomal protein S25 (eS25). Additionally, a mechanistic and mutational analysis revealed that the HIV-1 IRES is modular in nature and that once the 40S ribosomal subunit is recruited to the IRES, translation initiates without the need of ribosome scanning. These findings elucidate a mechanism of initiation by the HIV-1 IRES whereby a number of highly structured sites present within the HIV-1 5' leader leads to the recruitment of the 40S subunit directly at the site of initiation of protein synthesis.
authors.affiliation: Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Carvajal
authors.affiliation: Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Maricarmen
authors.initials: M
authors.lastname: Vallejos
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, AL, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Walters
authors.affiliation: Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Nataly
authors.initials: N
authors.lastname: Contreras
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, AL, USA.
authors.forename: Marla I
authors.initials: MI
authors.lastname: Hertz
authors.affiliation: Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Olivares
authors.affiliation: Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Cáceres
authors.affiliation: Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Karla
authors.initials: K
authors.lastname: Pino
authors.affiliation: Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Letelier
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, AL, USA.
authors.forename: Sunnie R
authors.initials: SR
authors.lastname: Thompson
authors.affiliation: Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Marcelo
authors.initials: M
authors.lastname: López-Lastra
mesh_terms: D020121:5' Untranslated Regions / Q000187:drug effects / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004486:Edeine / Q000494:pharmacology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D000072417:Protein Domains; D012333:RNA, Messenger / Q000235:genetics*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020121:5' Untranslated Regions; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; C489168:RPS25 protein, human; D012269:Ribosomal Proteins; D014764:Viral Proteins; D004486:Edeine
keywords: HIV-1; RNA; internal ribosomal entry site; protein synthesis