title: RNA-Associated Early-Stage Antiviral Factor Is a Major Component of Lv2 Restriction.
abstract: Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication in human cells is restricted at early postentry steps by host inhibitory factors. We previously described and characterized an early-phase restriction of HIV-1 and -2 replication in human cell lines, primary macrophages, and peripheral blood mononuclear cells. The restriction was termed lentiviral restriction 2 (Lv2). The viral determinants of Lv2 susceptibility mapped to the HIV-2 envelope (Env) and capsid (CA). We subsequently reported a whole-genome small interfering RNA screening for factors involved in HIV that identified RNA-associated early-stage antiviral factor (REAF). Using HIV-2 chimeras of susceptible and nonsusceptible viruses, we show here that REAF is a major component of the previously described Lv2 restriction. Further studies of the viral CA demonstrate that the CA mutation I73V (previously called I207V), a potent determinant for HIV-2, is a weak determinant of susceptibility for HIV-1. More potent CA determinants for HIV-1 REAF restriction were identified at P38A, N74D, G89V, and G94D. These results firmly establish that in HIV-1, CA is a strong determinant of susceptibility to Lv2/REAF. Similar to HIV-2, HIV-1 Env can rescue sensitive CAs from restriction. We conclude that REAF is a major component of the previously described Lv2 restriction.IMPORTANCEMeasures taken by the host cell to combat infection drive the evolution of pathogens to counteract or sidestep them. The study of such virus-host conflicts can point to possible weaknesses in the arsenal of viruses and may lead to the rational design of antiviral agents. Here we describe our discovery that the host restriction factor REAF fulfills the same criteria previously used to describe lentiviral restriction (Lv2). We show that, like the HIV-2 CA, the CA of HIV-1 is a strong determinant of Lv2/REAF susceptibility. We illustrate how HIV counteracts Lv2/REAF by using an envelope with alternative routes of entry into cells.
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Marno
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Eithne
authors.initials: E
authors.lastname: O'Sullivan
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Jones
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Julieta
authors.initials: J
authors.lastname: Díaz-Delfín
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Pardieu
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Sloan
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom a.mcknight@qmul.ac.uk.
authors.forename: Áine
authors.initials: Á
authors.lastname: McKnight
mesh_terms: D000818:Animals; D036022:Capsid Proteins; D002460:Cell Line; D015686:Gene Products, env / Q000235:genetics; D016679:Genome, Viral; D015497:HIV-1 / Q000235:genetics; D015498:HIV-2 / Q000235:genetics; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007963:Leukocytes, Mononuclear / Q000821:virology; D011506:Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering; D014779:Virus Replication
chemical_list: D036022:Capsid Proteins; D015686:Gene Products, env; D011506:Proteins; D034741:RNA, Small Interfering
keywords: Lv2; REAF; antiviral