title: Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome.
abstract: BACKGROUND
  A modest change in HIV-1 fitness can have a significant impact on viral quasispecies evolution and viral pathogenesis, transmission and disease progression. To determine the impact of immune escape mutations selected by cytotoxic T lymphocytes (CTL) on viral fitness in the context of the cognate transmitted/founder (T/F) genome, we developed a new competitive fitness assay using molecular clones of T/F genomes lacking exogenous genetic markers and a highly sensitive and precise parallel allele-specific sequencing (PASS) method.
  
  
  RESULTS
  The T/F and mutant viruses were competed in CD4+ T-cell enriched cultures, relative proportions of viruses were assayed after repeated cell-free passage, and fitness costs were estimated by mathematical modeling. Naturally occurring HLA B57-restricted mutations involving the TW10 epitope in Gag and two epitopes in Tat/Rev and Env were assessed independently and together. Compensatory mutations which restored viral replication fitness were also assessed. A principal TW10 escape mutation, T242N, led to a 42% reduction in replication fitness but V247I and G248A mutations in the same epitope restored fitness to wild-type levels. No fitness difference was observed between the T/F and a naturally selected variant carrying the early CTL escape mutation (R355K) in Env and a reversion mutation in the Tat/Rev overlapping region.
  
  
  CONCLUSIONS
  These findings reveal a broad spectrum of fitness costs to CTL escape mutations in T/F viral genomes, similar to recent findings reported for neutralizing antibody escape mutations, and highlight the extraordinary plasticity and adaptive potential of the HIV-1 genome. Analysis of T/F genomes and their evolved progeny is a powerful approach for assessing the impact of composite mutational events on viral fitness.
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. fgao@duke.edu
authors.forename: Hongshuo
authors.initials: H
authors.lastname: Song
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pavlicek
authors.forename: Fangping
authors.initials: F
authors.lastname: Cai
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Bhattacharya
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Iyer
authors.forename: Katharine J
authors.initials: KJ
authors.lastname: Bar
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.forename: Nilu
authors.initials: N
authors.lastname: Goonetilleke
authors.forename: Michael K P
authors.initials: MK
authors.lastname: Liu
authors.forename: Anna
authors.initials: A
authors.lastname: Berg
authors.forename: Bhavna
authors.initials: B
authors.lastname: Hora
authors.forename: Mark S
authors.initials: MS
authors.lastname: Drinker
authors.forename: Josh
authors.initials: J
authors.lastname: Eudailey
authors.forename: Joy
authors.initials: J
authors.lastname: Pickeral
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.forename: Andrew
authors.initials: A
authors.lastname: McMichael
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
mesh_terms: D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D018703:Founder Effect; D056084:Genetic Fitness; D016679:Genome, Viral; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D014779:Virus Replication / Q000235:genetics*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054321:rev Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; C103707:HLA-B57 antigen; D054301:gag Gene Products, Human Immunodeficiency Virus; D054321:rev Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus