title: HLA-B57/B*5801 human immunodeficiency virus type 1 elite controllers select for rare gag variants associated with reduced viral replication capacity and strong cytotoxic T-lymphocyte [corrected] recognition.
abstract: Human immunodeficiency virus type 1 (HIV-1) elite controllers (EC) maintain viremia below the limit of commercial assay detection (<50 RNA copies/ml) in the absence of antiviral therapy, but the mechanisms of control remain unclear. HLA-B57 and the closely related allele B*5801 are particularly associated with enhanced control and recognize the same Gag(240-249) TW10 epitope. The typical escape mutation (T242N) within this epitope diminishes viral replication capacity in chronically infected persons; however, little is known about TW10 epitope sequences in residual replicating viruses in B57/B*5801 EC and the extent to which mutations within this epitope may influence steady-state viremia. Here we analyzed TW10 in a total of 50 B57/B*5801-positive subjects (23 EC and 27 viremic subjects). Autologous plasma viral sequences from both EC and viremic subjects frequently harbored the typical cytotoxic T-lymphocyte (CTL)-selected mutation T242N (15/23 sequences [65.2%] versus 23/27 sequences [85.1%], respectively; P = 0.18). However, other unique mutants were identified in HIV controllers, both within and flanking TW10, that were associated with an even greater reduction in viral replication capacity in vitro. In addition, strong CTL responses to many of these unique TW10 variants were detected by gamma interferon-specific enzyme-linked immunospot assay. These data suggest a dual mechanism for durable control of HIV replication, consisting of viral fitness loss resulting from CTL escape mutations together with strong CD8 T-cell immune responses to the arising variant epitopes.
authors.affiliation: Ragon Institute, Massachusetts General Hospital, 149 13th St., Room 5212, Charlestown, MA 02129, USA. miura523@hotmail.com
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miura
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: Arne
authors.initials: A
authors.lastname: Schneidewind
authors.forename: Michael
authors.initials: M
authors.lastname: Lobritz
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: Almas
authors.initials: A
authors.lastname: Rathod
authors.forename: Brian L
authors.initials: BL
authors.lastname: Block
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.forename: Brett
authors.initials: B
authors.lastname: Baker
authors.forename: Alissa C
authors.initials: AC
authors.lastname: Rothchild
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Alicja
authors.initials: A
authors.lastname: Trocha
authors.forename: Emily
authors.initials: E
authors.lastname: Cutrell
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Ildiko
authors.initials: I
authors.lastname: Toth
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Arts
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D015235:HLA-B Antigens / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D014779:Virus Replication / Q000235:genetics* / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; C500126:HLA-B*58:01 antigen; C103707:HLA-B57 antigen