title: Viral escape from dominant simian immunodeficiency virus epitope-specific cytotoxic T lymphocytes in DNA-vaccinated rhesus monkeys.
abstract: Virus-specific cytotoxic T lymphocytes (CTL) are critical for control of human immunodeficiency virus type 1 replication. However, viral escape from CTL recognition can undermine this immune control. Here we demonstrate the high frequency and pattern of viral escape from dominant epitope-specific CTL in SIV gag DNA-vaccinated rhesus monkeys following a heterologous simian immunodeficiency virus (SIV) challenge. DNA-vaccinated monkeys exhibited initial effective control of the SIV challenge, but this early control was lost by serial breakthroughs of viral replication over a 3-year follow-up period. Increases in plasma viral RNA correlated temporally with declines of dominant SIV epitope-specific CD8(+) T-lymphocyte responses and the emergence of viral mutations that escaped recognition by dominant epitope-specific CTL. Viral escape from CTL occurred in a total of seven of nine vaccinated and control monkeys, including three animals that initially controlled viral replication to undetectable levels of plasma viral RNA. These data suggest that CTL exert selective pressure on viral replication and that viral escape from CTL may be a limitation of CTL-based AIDS vaccine strategies.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. dbarouch@bidmc.harvard.edu
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kunstman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Glowczwskie
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Kunstman
authors.forename: Michael A
authors.initials: MA
authors.lastname: Egan
authors.forename: Fred W
authors.initials: FW
authors.lastname: Peyerl
authors.forename: Sampa
authors.initials: S
authors.lastname: Santra
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Kuroda
authors.forename: Jörn E
authors.initials: JE
authors.lastname: Schmitz
authors.forename: Kristin
authors.initials: K
authors.lastname: Beaudry
authors.forename: Georgia R
authors.initials: GR
authors.lastname: Krivulka
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lifton
authors.forename: Darci A
authors.initials: DA
authors.lastname: Gorgone
authors.forename: Steven M
authors.initials: SM
authors.lastname: Wolinsky
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D019143:Evolution, Molecular; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D008253:Macaca mulatta; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D017931:DNA Primers; D016056:Immunodominant Epitopes; D019444:Vaccines, DNA; D014765:Viral Vaccines