title: Cytotoxic T-lymphocyte escape does not always explain the transient control of simian immunodeficiency virus SIVmac239 viremia in adenovirus-boosted and DNA-primed Mamu-A*01-positive rhesus macaques.
abstract: Adenovirus 5 (Ad5) vectors show promise as human immunodeficiency virus vaccine candidates. Indian rhesus macaques vaccinated with Ad5-gag controlled simian-human immunodeficiency virus SHIV89.6P viral replication in the absence of Env immunogens that might elicit humoral immunity. Here we immunized 15 macaques using either a homologous Ad5-gag/Ad5-gag (Ad5/Ad5) or a heterologous DNA-gag/Ad5-gag (DNA/Ad5) prime-boost regimen and challenged them with a high dose of simian immunodeficiency virus SIVmac239. Macaques vaccinated with the DNA/Ad5 regimen experienced a brief viral load nadir of less than 10,000 viral copies per ml blood plasma that was not seen in Mamu-A*01-negative DNA/Ad5 vaccinees, Mamu-A*01-positive Ad5/Ad5 vaccinees, or vaccine-naive controls. Interestingly, most of these animals were not durably protected from disease progression when challenged with SIVmac239. To investigate the reasons underlying this short-lived vaccine effect, we investigated breadth of the T-cell response, immunogenetic background, and viral escape from CD8+ lymphocytes that recognize immunodominant T-cell epitopes. We show that these animals do not mount unusually broad cellular immune response, nor do they express unusual major histocompatibility complex class I alleles. Viral recrudescence occurred in four of the five Mamu-A*01-positive vaccinated macaques. However, only a single animal in this group demonstrated viral escape in the immunodominant Gag181-189 CM9 response. These results suggest that viral "breakthrough" in vaccinated animals and viral escape are not inextricably linked and underscore the need for additional research into the mechanisms of vaccine failure.
authors.affiliation: Wisconsin National Primate Center, 1220 Capitol Court, Madison, WI 53715, USA.
authors.forename: Adrian B
authors.initials: AB
authors.lastname: McDermott
authors.forename: David H
authors.initials: DH
authors.lastname: O'Connor
authors.forename: Sarah
authors.initials: S
authors.lastname: Fuenger
authors.forename: Shari
authors.initials: S
authors.lastname: Piaskowski
authors.forename: Sarah
authors.initials: S
authors.lastname: Martin
authors.forename: John
authors.initials: J
authors.lastname: Loffredo
authors.forename: Matthew
authors.initials: M
authors.lastname: Reynolds
authors.forename: Jason
authors.initials: J
authors.lastname: Reed
authors.forename: Jessica
authors.initials: J
authors.lastname: Furlott
authors.forename: Timothy
authors.initials: T
authors.lastname: Jacoby
authors.forename: Cara
authors.initials: C
authors.lastname: Riek
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dodds
authors.forename: Kendall
authors.initials: K
authors.lastname: Krebs
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Davies
authors.forename: William A
authors.initials: WA
authors.lastname: Schleif
authors.forename: Danilo R
authors.initials: DR
authors.lastname: Casimiro
authors.forename: John W
authors.initials: JW
authors.lastname: Shiver
authors.forename: D I
authors.initials: DI
authors.lastname: Watkins
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D015683:Gene Products, gag / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000302:isolation & purification; D008253:Macaca mulatta; D011995:Recombination, Genetic; D018449:SAIDS Vaccines / Q000008:administration & dosage* / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology; D019562:Viral Load; D014766:Viremia / Q000276:immunology* / Q000473:pathology
chemical_list: D000914:Antibodies, Viral; D015683:Gene Products, gag; D015395:Histocompatibility Antigens Class I; C110764:Mamu-A 01 antigen; D018449:SAIDS Vaccines; D019444:Vaccines, DNA