title: Envelope variants circulating as initial neutralization breadth developed in two HIV-infected subjects stimulate multiclade neutralizing antibodies in rabbits.
abstract: Identifying characteristics of the human immunodeficiency virus type 1 (HIV-1) envelope that are effective in generating broad, protective antibodies remains a hurdle to HIV vaccine design. Emerging evidence of the development of broad and potent neutralizing antibodies in HIV-infected subjects suggests that founder and subsequent progeny viruses may express unique antigenic motifs that contribute to this developmental pathway. We hypothesize that over the course of natural infection, B cells are programmed to develop broad antibodies by exposure to select populations of emerging envelope quasispecies variants. To test this hypothesis, we identified two unrelated subjects whose antibodies demonstrated increasing neutralization breadth against a panel of HIV-1 isolates over time. Full-length functional env genes were cloned longitudinally from these subjects from months after infection through 2.6 to 5.8 years of infection. Motifs associated with the development of breadth in published, cross-sectional studies were found in both subjects. We compared the immunogenicity of envelope vaccines derived from time points obtained during and after broadening of neutralization activity within these subjects. Rabbits were coimmunized four times with selected multiple gp160 DNAs and gp140-trimeric envelope proteins. The affinity of the polyclonal response increased as a function of boosting. The most rapid and persistent neutralization of multiclade tier 1 viruses was elicited by envelopes that were circulating in plasma at time points prior to the development of 50% neutralization breadth in both human subjects. The breadth elicited in rabbits was not improved by exposure to later envelope variants. These data have implications for vaccine development in describing a target time point to identify optimal envelope immunogens.
  
  
  OBJECTIVE
  Vaccine protection against viral infections correlates with the presence of neutralizing antibodies; thus, vaccine components capable of generating potent neutralization are likely to be critical constituents in an effective HIV vaccine. However, vaccines tested thus far have elicited only weak antibody responses and very modest, waning protection. We hypothesized that B cells develop broad antibodies by exposure to the evolving viral envelope population and tested this concept using multiple envelopes from two subjects who developed neutralization breadth within a few years of infection. We compared different combinations of envelopes from each subject to identify the most effective immunogens and regimens. In each subject, use of HIV envelopes circulating during the early development and maturation of breadth generated more-potent antibodies that were modestly cross neutralizing. These data suggest a new approach to identifying envelope immunogens that may be more effective in generating protective antibodies in humans.
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.
authors.forename: Delphine C
authors.initials: DC
authors.lastname: Malherbe
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA U.S. Military HIV Research Program, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Franco
authors.initials: F
authors.lastname: Pissani
authors.affiliation: Seattle Biomed, Seattle, Washington, USA.
authors.forename: D Noah
authors.initials: DN
authors.lastname: Sather
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.
authors.forename: Biwei
authors.initials: B
authors.lastname: Guo
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Pandey
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Sutton
authors.affiliation: Seattle Biomed, Seattle, Washington, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Stuart
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Harlan
authors.initials: H
authors.lastname: Robins
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.
authors.forename: Byung
authors.initials: B
authors.lastname: Park
authors.affiliation: U.S. Military HIV Research Program, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Shelly J
authors.initials: SJ
authors.lastname: Krebs
authors.affiliation: GE Healthcare, Life Sciences, Piscataway, New Jersey, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Schuman
authors.affiliation: Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Spyros
authors.initials: S
authors.lastname: Kalams
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Hessell
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, USA haigwoon@ohsu.edu.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Haigwood
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D005260:Female; D015483:HIV Antibodies / Q000097:blood*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000235:genetics; D011817:Rabbits; D017422:Sequence Analysis, DNA; D054299:env Gene Products, Human Immunodeficiency Virus / 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