title: Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8+ T-Cell Responses Focused on a Single Nef Epitope Select for Escape Variants Shortly after Infection.
abstract: Certain major histocompatibility complex class I (MHC-I) alleles (e.g., HLA-B*27) are enriched among human immunodeficiency virus type 1 (HIV-1)-infected individuals who suppress viremia without treatment (termed "elite controllers" [ECs]). Likewise, Mamu-B*08 expression also predisposes rhesus macaques to control simian immunodeficiency virus (SIV) replication. Given the similarities between Mamu-B*08 and HLA-B*27, SIV-infected Mamu-B*08(+) animals provide a model to investigate HLA-B*27-mediated elite control. We have recently shown that vaccination with three immunodominant Mamu-B*08-restricted epitopes (Vif RL8, Vif RL9, and Nef RL10) increased the incidence of elite control in Mamu-B*08(+) macaques after challenge with the pathogenic SIVmac239 clone. Furthermore, a correlate analysis revealed that CD8(+) T cells targeting Nef RL10 was correlated with improved outcome. Interestingly, this epitope is conserved between SIV and HIV-1 and exhibits a delayed and atypical escape pattern. These features led us to postulate that a monotypic vaccine-induced Nef RL10-specific CD8(+) T-cell response would facilitate the development of elite control in Mamu-B*08(+) animals following repeated intrarectal challenges with SIVmac239. To test this, we vaccinated Mamu-B*08(+) animals with nef inserts in which Nef RL10 was either left intact (group 1) or disrupted by mutations (group 2). Although monkeys in both groups mounted Nef-specific cellular responses, only those in group 1 developed Nef RL10-specific CD8(+) T cells. These vaccine-induced effector memory CD8(+) T cells did not prevent infection. Escape variants emerged rapidly in the group 1 vaccinees, and ultimately, the numbers of ECs were similar in groups 1 and 2. High-frequency vaccine-induced CD8(+) T cells focused on a single conserved epitope and therefore did not prevent infection or increase the incidence of elite control in Mamu-B*08(+) macaques.
  
  
  OBJECTIVE
  Since elite control of chronic-phase viremia is a classic example of an effective immune response against HIV/SIV, elucidating the basis of this phenomenon may provide useful insights into how to elicit such responses by vaccination. We have previously established that vaccine-induced CD8(+) T-cell responses against three immunodominant epitopes can increase the incidence of elite control in SIV-infected Mamu-B*08(+) rhesus macaques—a model of HLA-B*27-mediated elite control. Here, we investigated whether a monotypic vaccine-induced CD8(+) T-cell response targeting the conserved "late-escaping" Nef RL10 epitope can increase the incidence of elite control in Mamu-B*08(+) monkeys. Surprisingly, vaccine-induced Nef RL10-specific CD8(+) T cells selected for variants within days after infection and, ultimately, did not facilitate the development of elite control. Elite control is, therefore, likely to involve CD8(+) T-cell responses against more than one epitope. Together, these results underscore the complexity and multidimensional nature of virologic control of lentivirus infection.
authors: Department of Pathology, University of Miami, Miami, Florida, USA mmartins@med.miami.edu.
authors: Mauricio A
authors: MA
authors: Martins
authors: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Damien C
authors: DC
authors: Tully
authors: Department of Pathology, University of Miami, Miami, Florida, USA.
authors: Michael A
authors: MA
authors: Cruz
authors: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Karen A
authors: KA
authors: Power
authors: Department of Pathology, University of Miami, Miami, Florida, USA.
authors: Marlon G
authors: MG
authors: Veloso de Santana
authors: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors: David J
authors: DJ
authors: Bean
authors: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Colin B
authors: CB
authors: Ogilvie
authors: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Rujuta
authors: R
authors: Gadgil
authors: Laboratório de Biologia Molecular de Flavivirus, Instituto Oswaldo Cruz-FIOCRUZ, Rio de Janeiro, Brazil.
authors: Noemia S
authors: NS
authors: Lima
authors: Department of Pathology, University of Miami, Miami, Florida, USA.
authors: Diogo M
authors: DM
authors: Magnani
authors: Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Keisuke
authors: K
authors: Ejima
authors: Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: David B
authors: DB
authors: Allison
authors: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
authors: Michael
authors: M
authors: Piatak
authors: Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA.
authors: John D
authors: JD
authors: Altman
authors: International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory, Brooklyn Army Terminal, Brooklyn, New York, USA.
authors: Christopher L
authors: CL
authors: Parks
authors: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Eva G
authors: EG
authors: Rakasz
authors: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Saverio
authors: S
authors: Capuano
authors: Instituto de Tecnologia em Imunobiológicos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors: Ricardo
authors: R
authors: Galler
authors: Laboratório de Biologia Molecular de Flavivirus, Instituto Oswaldo Cruz-FIOCRUZ, Rio de Janeiro, Brazil.
authors: Myrna C
authors: MC
authors: Bonaldo
authors: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
authors: Jeffrey D
authors: JD
authors: Lifson
authors: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Todd M
authors: TM
authors: Allen
authors: Department of Pathology, University of Miami, Miami, Florida, USA.
authors: David I
authors: DI
authors: Watkins
mesh_terms: D000818:Animals; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018449:SAIDS Vaccines / Q000276:immunology*; D017422:Sequence Analysis, DNA; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D018709:Statistics, Nonparametric; D014611:Vaccination; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics*
chemical_list: D017931:DNA Primers; D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen; D015395:Histocompatibility Antigens Class I; C429284:NEF protein, SIV; D018449:SAIDS Vaccines; D054334:Viral Regulatory and Accessory Proteins