title: Sequential immunization with a subtype B HIV-1 envelope quasispecies partially mimics the in vivo development of neutralizing antibodies.
abstract: A major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is the design of Envelope (Env)-based immunogens effective at eliciting heterologous or broad neutralizing antibodies (NAbs). We hypothesized that programming the B-cell response could be achieved by sequentially exposing the host to a collection of env variants representing the viral quasispecies members isolated from an individual that developed broad NAbs over time. This ordered vaccine approach (sequential) was compared to exposure to a cocktail of env clones (mixture) and to a single env variant (clonal). The three strategies induced comparable levels of the autologous and heterologous neutralization of tier 1 pseudoviruses. Sequential and mixture exposure to quasispecies led to epitope targeting similar to that observed in the simian-human immunodeficiency virus (SHIV)-infected animal from which the env variants were cloned, while clonal and sequential exposure led to greater antibody maturation than the mixture. Therefore, the sequential vaccine approach best replicated the features of the NAb response observed in that animal. This study is the first to explore the use of a collection of HIV-1 env quasispecies variants as immunogens and to present evidence that it is possible to educate the B-cell response by sequential exposure to native HIV-1 quasispecies env variants derived from an individual with a broadened NAb response.
authors.affiliation: Oregon National Primate Center, Oregon Health and Science University, Beaverton, Oregon 97006, USA.
authors.forename: Delphine C
authors.initials: DC
authors.lastname: Malherbe
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Doria-Rose
authors.forename: Lynda
authors.initials: L
authors.lastname: Misher
authors.forename: Travis
authors.initials: T
authors.lastname: Beckett
authors.forename: Wendy Blay
authors.initials: WB
authors.lastname: Puryear
authors.forename: Jason T
authors.initials: JT
authors.lastname: Schuman
authors.forename: Zane
authors.initials: Z
authors.lastname: Kraft
authors.forename: Jean
authors.initials: J
authors.lastname: O'Malley
authors.forename: Motomi
authors.initials: M
authors.lastname: Mori
authors.forename: Indresh
authors.initials: I
authors.lastname: Srivastava
authors.forename: Susan
authors.initials: S
authors.lastname: Barnett
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Haigwood
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D015483:HIV Antibodies / Q000097:blood*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization / Q000379:methods*; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D012367:RNA, Viral / Q000235:genetics; D011817:Rabbits; D017422:Sequence Analysis, DNA; D054299:env Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D012367:RNA, Viral; D054299:env Gene Products, Human Immunodeficiency Virus