title: Multiple low-dose challenges in a rhesus macaque AIDS vaccine trial result in an evolving host response that affects protective outcome.
abstract: Using whole-blood transcriptional profiling, we investigated differences in the host response to vaccination and challenge in a rhesus macaque AIDS vaccine trial. Samples were collected from animals prior to and after vaccination with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig loaded with simian immunodeficiency virus (SIV) peptides, either alone or in combination with a SIV-gp120 protein boost. Additional samples were collected following multiple low-dose rectal challenges with SIVmac251. Animals in the boosted group had a 73% reduced risk of infection. Surprisingly, few changes in gene expression were observed during the vaccination phase. Focusing on postchallenge comparisons, in particular for protected animals, we identified a host response signature of protection comprised of strong interferon signaling after the first challenge, which then largely abated after further challenges. We also identified a host response signature, comprised of early macrophage-mediated inflammatory responses, in animals with undetectable viral loads 5 days after the first challenge but with unusually high viral titers after subsequent challenges. Statistical analysis showed that prime-boost vaccination significantly lowered the probability of infection in a time-consistent manner throughout several challenges. Given that humoral responses in the prime-boost group were highly significant prechallenge correlates of protection, the strong innate signaling after the first challenge suggests that interferon signaling may enhance vaccine-induced antibody responses and is an important contributor to protection from infection during repeated low-dose exposure to SIV.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Selinger
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Natasa
authors.initials: N
authors.lastname: Strbo
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Gonzalez
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Lauri
authors.initials: L
authors.lastname: Aicher
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: G Lynn
authors.initials: GL
authors.lastname: Law
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA Washington National Primate Research Center, University of Washington, Seattle, Washington, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Palermo
authors.affiliation: Animal Models and Retroviral Vaccines, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Vaccari
authors.affiliation: Animal Models and Retroviral Vaccines, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Franchini
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Eckhard R
authors.initials: ER
authors.lastname: Podack
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA Washington National Primate Research Center, University of Washington, Seattle, Washington, USA honey@uw.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D005260:Female; D054884:Host-Pathogen Interactions; D008253:Macaca mulatta; D008297:Male; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control; D015302:Simian Immunodeficiency Virus / Q000235:genetics; D014611:Vaccination
chemical_list: D016915:AIDS Vaccines; D000914:Antibodies, Viral; D018449:SAIDS Vaccines