title: Selection on the human immunodeficiency virus type 1 proteome following primary infection.
abstract: Typically during human immunodeficiency virus type 1 (HIV-1) infection, a nearly homogeneous viral population first emerges and then diversifies over time due to selective forces that are poorly understood. To identify these forces, we conducted an intensive longitudinal study of viral genetic changes and T-cell immunity in one subject at < or =17 time points during his first 3 years of infection, and in his infecting partner near the time of transmission. Autologous peptides covering amino acid sites inferred to be under positive selection were powerful for identifying HIV-1-specific cytotoxic-T-lymphocyte (CTL) epitopes. Positive selection and mutations resulting in escape from CTLs occurred across the viral proteome. We detected 25 CTL epitopes, including 14 previously unreported. Seven new epitopes mapped to the viral Env protein, emphasizing Env as a major target of CTLs. One-third of the selected sites were associated with epitopic mutational escapes from CTLs. Most of these resulted from replacement with amino acids found at low database frequency. Another one-third represented acquisition of amino acids found at high database frequency, suggesting potential reversions of CTL epitopic sites recognized by the immune system of the transmitting partner and mutation toward improved viral fitness in the absence of immune targeting within the recipient. A majority of the remaining selected sites occurred in the envelope protein and may have been subjected to humoral immune selection. Hence, a majority of the amino acids undergoing selection in this subject appeared to result from fitness-balanced CTL selection, confirming CTLs as a dominant selective force in HIV-1 infection.
authors.affiliation: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195-8070, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: McNevin
authors.forename: Jianhong
authors.initials: J
authors.lastname: Cao
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Indira
authors.initials: I
authors.lastname: Genowati
authors.forename: Kim
authors.initials: K
authors.lastname: Wong
authors.forename: Sherry
authors.initials: S
authors.lastname: McLaughlin
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McSweyn
authors.forename: Kurt
authors.initials: K
authors.lastname: Diem
authors.forename: Claire E
authors.initials: CE
authors.lastname: Stevens
authors.forename: Janine
authors.initials: J
authors.lastname: Maenza
authors.forename: Hongxia
authors.initials: H
authors.lastname: He
authors.forename: David C
authors.initials: DC
authors.lastname: Nickle
authors.forename: Daniel
authors.initials: D
authors.lastname: Shriner
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Holte
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
mesh_terms: D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020543:Proteome / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D012641:Selection, Genetic; D013997:Time Factors
chemical_list: D000939:Epitopes; D020543:Proteome