title: Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection.
abstract: Identification of full-length transmitted HIV-1 genomes could be instrumental in HIV-1 pathogenesis, microbicide, and vaccine research by enabling the direct analysis of those viruses actually responsible for productive clinical infection. We show in 12 acutely infected subjects (9 clade B and 3 clade C) that complete HIV-1 genomes of transmitted/founder viruses can be inferred by single genome amplification and sequencing of plasma virion RNA. This allowed for the molecular cloning and biological analysis of transmitted/founder viruses and a comprehensive genome-wide assessment of the genetic imprint left on the evolving virus quasispecies by a composite of host selection pressures. Transmitted viruses encoded intact canonical genes (gag-pol-vif-vpr-tat-rev-vpu-env-nef) and replicated efficiently in primary human CD4(+) T lymphocytes but much less so in monocyte-derived macrophages. Transmitted viruses were CD4 and CCR5 tropic and demonstrated concealment of coreceptor binding surfaces of the envelope bridging sheet and variable loop 3. 2 mo after infection, transmitted/founder viruses in three subjects were nearly completely replaced by viruses differing at two to five highly selected genomic loci; by 12-20 mo, viruses exhibited concentrated mutations at 17-34 discrete locations. These findings reveal viral properties associated with mucosal HIV-1 transmission and a limited set of rapidly evolving adaptive mutations driven primarily, but not exclusively, by early cytotoxic T cell responses.
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Jesus F
authors.initials: JF
authors.lastname: Salazar-Gonzalez
authors.forename: Maria G
authors.initials: MG
authors.lastname: Salazar
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Learn
authors.forename: Elena E
authors.initials: EE
authors.lastname: Giorgi
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.forename: Shuyi
authors.initials: S
authors.lastname: Wang
authors.forename: Joshua
authors.initials: J
authors.lastname: Baalwa
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Kraus
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parrish
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Shaw
authors.forename: M Brad
authors.initials: MB
authors.lastname: Guffey
authors.forename: Katharine J
authors.initials: KJ
authors.lastname: Bar
authors.forename: Katie L
authors.initials: KL
authors.lastname: Davis
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer-Jambor
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.forename: Michael S
authors.initials: MS
authors.lastname: Saag
authors.forename: Myron S
authors.initials: MS
authors.lastname: Cohen
authors.forename: Joseph
authors.initials: J
authors.lastname: Mulenga
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
authors.forename: Susan
authors.initials: S
authors.lastname: Allen
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: Peter
authors.initials: P
authors.lastname: Hraber
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Bhattacharya
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Bette T
authors.initials: BT
authors.lastname: Korber
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D019143:Evolution, Molecular; D005260:Female; D016679:Genome, Viral; D015658:HIV Infections / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D016013:Likelihood Functions; D008264:Macrophages / Q000276:immunology / Q000821:virology; D008297:Male; D008962:Models, Theoretical; D009154:Mutation; D010641:Phenotype; D010802:Phylogeny; D019713:Receptors, CCR5 / Q000276:immunology; D014771:Virion / Q000235:genetics; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
chemical_list: D019713:Receptors, CCR5