title: Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation.
abstract: BACKGROUND
  Fitness costs and slower disease progression are associated with a cytolytic T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains on the fitness costs due to the T242N mutation has not been well characterized. To better understand the extent of fitness costs of the T242N mutation and the repair of fitness loss through compensatory amino acids, we investigated its fitness impact in different transmitted/founder (T/F) viruses.
  
  
  RESULTS
  The T242N mutation resulted in various levels of fitness loss in four different T/F viruses. However, the fitness costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover, the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome resulted in significant fitness cost, suggesting the fitness loss caused by the T242N mutation had been fully repaired in the donor at transmission. Analysis of the global circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high prevalence of compensatory amino acids for the T242N mutation and other T cell escape mutations.
  
  
  CONCLUSIONS
  Our results show that the preexisting compensatory amino acids in the majority of circulating HIV-1 strains could significantly compromise the fitness loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, 27710, USA. ldl198653@126.com.|National Engineering Laboratory For AIDS Vaccine, College of Life Science, Jilin University, Changchun, 130012, Jilin, China. ldl198653@126.com.
authors.forename: Donglai
authors.initials: D
authors.lastname: Liu
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, 27710, USA. ootaoz@aliyun.com.|National Engineering Laboratory For AIDS Vaccine, College of Life Science, Jilin University, Changchun, 130012, Jilin, China. ootaoz@aliyun.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Zuo
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, 27710, USA. bhavna.hora@dm.duke.edu.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Hora
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, 27710, USA. hongshuo.song@dm.duke.edu.
authors.forename: Hongshuo
authors.initials: H
authors.lastname: Song
authors.affiliation: National Engineering Laboratory For AIDS Vaccine, College of Life Science, Jilin University, Changchun, 130012, Jilin, China. weikong@mail.jlu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.affiliation: National Engineering Laboratory For AIDS Vaccine, College of Life Science, Jilin University, Changchun, 130012, Jilin, China. xianghui@jlu.edu.cn.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Microbiology, Immunology and Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. nilu_goonetilleke@med.unc.edu.
authors.forename: Nilu
authors.initials: N
authors.lastname: Goonetilleke
authors.affiliation: Theoretical Division, Los Alamos National laboratory, Los Alamos, NM, 87545, USA. tanmoy@lanl.gov.
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Bhattacharya
authors.affiliation: Theoretical Division, Los Alamos National laboratory, Los Alamos, NM, 87545, USA. asp@lanl.gov.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, 27710, USA. barton.haynes@dm.duke.edu.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Weatherall Institute of molecular Medicine, University of Oxford, Oxford, OX3 9DS, England, UK. andrew.mcmichael@ndm.ox.ac.uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, 27710, USA. fgao@duke.edu.|National Engineering Laboratory For AIDS Vaccine, College of Life Science, Jilin University, Changchun, 130012, Jilin, China. fgao@duke.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
mesh_terms: D000596:Amino Acids / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D057131:Immune Evasion; D020125:Mutation, Missense; D013601:T-Lymphocytes / Q000276:immunology*; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000596:Amino Acids; D054301:gag Gene Products, Human Immunodeficiency Virus