title: Evolutionary analysis identifies an MX2 haplotype associated with natural resistance to HIV-1 infection.
abstract: The protein product of the myxovirus resistance 2 (MX2) gene restricts HIV-1 and simian retroviruses. We demonstrate that MX2 evolved adaptively in mammals with distinct sites representing selection targets in distinct branches; selection mainly involved residues in loop 4, previously shown to carry antiviral determinants. Modeling data indicated that positively selected sites form a continuous surface on loop 4, which folds into two antiparallel α-helices protruding from the stalk domain. A population genetics-phylogenetics approach indicated that the coding region of MX2 mainly evolved under negative selection in the human lineage. Nonetheless, population genetic analyses demonstrated that natural selection operated on MX2 during the recent history of human populations: distinct selective events drove the frequency increase of two haplotypes in the populations of Asian and European ancestry. The Asian haplotype carries a susceptibility allele for melanoma; the European haplotype is tagged by rs2074560, an intronic variant. Analyses performed on three independent European cohorts of HIV-1-exposed seronegative individuals with different geographic origin and distinct exposure route showed that the ancestral (G) allele of rs2074560 protects from HIV-1 infection with a recessive effect (combined P = 1.55 × 10(-4)). The same allele is associated with lower in vitro HIV-1 replication and increases MX2 expression levels in response to IFN-α. Data herein exploit evolutionary information to identify a novel host determinant of HIV-1 infection susceptibility.
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy manuela.sironi@bp.lnf.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Gnudi
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Irma
authors.initials: I
authors.lastname: Saulle
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Salomè
authors.initials: S
authors.lastname: Ibba
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Filippi
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Yahyaei
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Tresoldi
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Riva
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Trabattoni
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: De Gioia
authors.affiliation: S. Maria Annunziata Hospital, Florence, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lo Caputo
authors.affiliation: S. Maria Annunziata Hospital, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mazzotta
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pontremoli
authors.affiliation: Infectious Diseases and Microbiology Clinical Unit, Valme Hospital, Seville, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Pineda
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.affiliation: Maimonides Institut for Biomedical Research (IMIBIC), Reina Sofia Universitary Hospital, University of Cordoba, Cordoba, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rivero-Juarez
authors.affiliation: Immunogenetics Unit, Department of Experimental Biology, University of Jaen, Jaen, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Caruz
authors.affiliation: Department of Physiopathology and Transplantation, University of Milan, Milan, ItalyDon C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D044466:Asian People / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D060467:Disease Resistance; D019143:Evolution, Molecular; D014644:Genetic Variation; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology*; D015497:HIV-1 / Q000472:pathogenicity; D006239:Haplotypes; D006801:Humans; D008957:Models, Genetic; D064547:Myxovirus Resistance Proteins / Q000737:chemistry / Q000235:genetics*; D010802:Phylogeny; D012641:Selection, Genetic; D044465:White People / Q000235:genetics*
chemical_list: C579068:MX2 protein, human; D064547:Myxovirus Resistance Proteins
keywords: HIV-1 infection; MX2; adaptive evolution; positive selection