title: Acute phase CD8+ T lymphocytes against alternate reading frame epitopes select for rapid viral escape during SIV infection.
abstract: CD8+ T Lymphocytes (CTL) can control AIDS virus replication. However, natural selection favoring viral variants that escape CTL recognition is a common feature of both simian immunodeficiency virus (SIV) infection of macaques and HIV infection of humans. Emerging data indicate that CTL directed against alternate reading frame (ARF)-derived epitopes (a.k.a. cryptic epitopes) are important components of the total virus-specific response in SIV and HIV infection but the contributions of these responses during the critical first several weeks of infection have not been determined. We used a focused deep sequencing approach to examine acute phase viral evolution in response to CTL targeting two polypeptides encoded by ARFs of SIVmac239 in SIV-infected rhesus macaques. We report high magnitude CTL responses as early as three weeks post-infection against epitopes within both ARFs, which both overlap the 5' end of the env gene. Further, mutations accumulated in the epitopes by three to four weeks post infection consistent with viral escape. Interestingly, these mutations largely maintained the primary amino acid sequence of the overlapping Envelope protein. Our data show that high frequency CTL target cryptic epitopes and exert selective pressure on SIV during the acute phase, underscoring the importance of these unique immune responses.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Walsh
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Bimber
authors.forename: Arpita
authors.initials: A
authors.lastname: Das
authors.forename: Shari M
authors.initials: SM
authors.lastname: Piaskowski
authors.forename: Eva G
authors.initials: EG
authors.lastname: Rakasz
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Bean
authors.forename: Philip A
authors.initials: PA
authors.lastname: Mudd
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Ericsen
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Wilson
authors.forename: Austin L
authors.initials: AL
authors.lastname: Hughes
authors.forename: David H
authors.initials: DH
authors.lastname: O'Connor
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maness
mesh_terms: D000210:Acute-Phase Reaction; D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D019143:Evolution, Molecular; D057131:Immune Evasion; D007700:Kinetics; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D014759:Viral Envelope Proteins