title: Vaccination with Gag, Vif, and Nef gene fragments affords partial control of viral replication after mucosal challenge with SIVmac239.
abstract: Broadly targeted cellular immune responses are thought to be important for controlling replication of human and simian immunodeficiency viruses (HIV and SIV). However, eliciting such responses by vaccination is complicated by immunodominance, the preferential targeting of only a few of the many possible epitopes of a given antigen. This phenomenon may be due to the coexpression of dominant and subdominant epitopes by the same antigen-presenting cell and may be overcome by distributing these sequences among several different vaccine constructs. Accordingly, we tested whether vaccinating rhesus macaques with "minigenes" encoding fragments of Gag, Vif, and Nef resulted in broadened cellular responses capable of controlling SIV replication. We delivered these minigenes through combinations of recombinant Mycobacterium bovis BCG (rBCG), electroporated recombinant DNA (rDNA) along with an interleukin-12 (IL-12)-expressing plasmid (EP rDNA plus pIL-12), yellow fever vaccine virus 17D (rYF17D), and recombinant adenovirus serotype 5 (rAd5). Although priming with EP rDNA plus pIL-12 increased the breadth of vaccine-induced T-cell responses, this effect was likely due to the improved antigen delivery afforded by electroporation rather than modulation of immunodominance. Indeed, Mamu-A*01(+) vaccinees mounted CD8(+) T cells directed against only one subdominant epitope, regardless of the vaccination regimen. After challenge with SIVmac239, vaccine efficacy was limited to a modest reduction in set point in some of the groups and did not correlate with standard T-cell measurements. These findings suggest that broad T-cell responses elicited by conventional vectors may not be sufficient to substantially contain AIDS virus replication.
  
  
  OBJECTIVE
  Immunodominance poses a major obstacle to the generation of broadly targeted, HIV-specific cellular responses by vaccination. Here we attempted to circumvent this phenomenon and thereby broaden the repertoire of SIV-specific cellular responses by vaccinating rhesus macaques with minigenes encoding fragments of Gag, Vif, and Nef. In contrast to previous mouse studies, this strategy appeared to minimally affect monkey CD8(+) T-cell immundominance hierarchies, as seen by the detection of only one subdominant epitope in Mamu-A*01(+) vaccinees. This finding underscores the difficulty of inducing subdominant CD8(+) T cells by vaccination and demonstrates that strategies other than gene fragmentation may be required to significantly alter immunodominance in primates. Although some of the regimens tested here were extremely immunogenic, vaccine efficacy was limited to a modest reduction in set point viremia after challenge with SIVmac239. No correlates of protection were identified. These results reinforce the notion that vaccine immunogenicity does not predict control of AIDS virus replication.
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Mauricio A
authors.initials: MA
authors.lastname: Martins
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Wilson
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Shari M
authors.initials: SM
authors.lastname: Piaskowski
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Kim L
authors.initials: KL
authors.lastname: Weisgrau
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Furlott
authors.affiliation: Laboratório de Biologia Molecular de Flavivírus, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Myrna C
authors.initials: MC
authors.lastname: Bonaldo
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Marlon G
authors.initials: MG
authors.lastname: Veloso de Santana
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Rudersdorf
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Eva G
authors.initials: EG
authors.lastname: Rakasz
authors.affiliation: Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Karen D
authors.initials: KD
authors.lastname: Keating
authors.affiliation: International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory, Brooklyn Army Terminal, Brooklyn, New York, USA.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Chiuchiolo
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Allison
authors.affiliation: International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory, Brooklyn Army Terminal, Brooklyn, New York, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Parks
authors.affiliation: Instituto de Tecnologia em Imunobiológicos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Galler
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA dwatkins@med.miami.edu.
authors.forename: David I
authors.initials: DI
authors.lastname: Watkins
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology*; D015693:Gene Products, nef / Q000235:genetics / Q000276:immunology*; D016346:Gene Products, vif / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors / Q000008:administration & dosage*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D008253:Macaca mulatta / Q000821:virology; D008297:Male; D051379:Mice; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000627:therapeutic use*; D014779:Virus Replication
chemical_list: D015683:Gene Products, gag; D015693:Gene Products, nef; D016346:Gene Products, vif; D015395:Histocompatibility Antigens Class I; C092249:Mamu-B 01 antigen, Macaca mulatta; D014614:Vaccines, Synthetic
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