title: CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller.
abstract: BACKGROUND
  Virus-specific T cells are critical components in the containment of immunodeficiency virus infections. While the protective role of CD8+ T cells is well established by studies of CD8+ T cell-mediated viral escape, it remains unknown if CD4+ T cells can also impose sufficient selective pressure on replicating virus to drive the emergence of high-frequency escape variants. Identifying a high frequency CD4+ T cell driven escape mutation would provide compelling evidence of direct immunological pressure mediated by these cells.
  
  
  RESULTS
  Here, we studied a SIVmac239-infected elite controller rhesus macaque with a 1,000-fold spontaneous increase in plasma viral load that preceded disease progression and death from AIDS-related complications. We sequenced the viral genome pre- and post-breakthrough and demonstrate that CD8+ T cells drove the majority of the amino acid substitutions outside of Env. However, within a region of Gag p27CA targeted only by CD4+ T cells, we identified a unique post-breakthrough mutation, Gag D205E, which abrogated CD4+ T cell recognition. Further, we demonstrate that the Gag p27CA-specific CD4+ T cells exhibited cytolytic activity and that SIV bearing the Gag D205E mutation escapes this CD4+ T cell effector function ex vivo.
  
  
  CONCLUSIONS
  Cumulatively, these results confirm the importance of virus specific CD8+ T cells and demonstrate that CD4+ T cells can also exert significant selective pressure on immunodeficiency viruses in vivo during low-level viral replication. These results also suggest that further studies of CD4+ T cell escape should focus on cases of elite control with spontaneous viral breakthrough.
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, 505 NW 185th, Beaverton, OR 97006, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Burwitz
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Giraldo-Vela
authors.forename: Jason
authors.initials: J
authors.lastname: Reed
authors.forename: Laura P
authors.initials: LP
authors.lastname: Newman
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Bean
authors.forename: Francesca A
authors.initials: FA
authors.lastname: Nimityongskul
authors.forename: Philip A
authors.initials: PA
authors.lastname: Castrovinci
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maness
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Leon
authors.forename: Richard
authors.initials: R
authors.lastname: Rudersdorf
authors.forename: Jonah B
authors.initials: JB
authors.lastname: Sacha
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015683:Gene Products, gag / Q000235:genetics; D016679:Genome, Viral; D057131:Immune Evasion / Q000235:genetics*; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D009154:Mutation; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D019562:Viral Load; D014766:Viremia / Q000276:immunology* / Q000473:pathology / Q000821:virology; D014779:Virus Replication / Q000235:genetics*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag