title: Comparable Antigenicity and Immunogenicity of Oligomeric Forms of a Novel, Acute HIV-1 Subtype C gp145 Envelope for Use in Preclinical and Clinical Vaccine Research.
abstract: Eliciting broadly reactive functional antibodies remains a challenge in human immunodeficiency virus type 1 (HIV-1) vaccine development that is complicated by variations in envelope (Env) subtype and structure. The majority of new global HIV-1 infections are subtype C, and novel antigenic properties have been described for subtype C Env proteins. Thus, an HIV-1 subtype C Env protein (CO6980v0c22) from an infected person in the acute phase (Fiebig stage I/II) was developed as a research reagent and candidate immunogen. The gp145 envelope is a novel immunogen with a fully intact membrane-proximal external region (MPER), extended by a polylysine tail. Soluble gp145 was enriched for trimers that yielded the expected "fan blade" motifs when visualized by cryoelectron microscopy. CO6980v0c22 gp145 reacts with the 4E10, PG9, PG16, and VRC01 HIV-1 neutralizing monoclonal antibodies (MAbs), as well as the V1/V2-specific PGT121, 697, 2158, and 2297 MAbs. Different gp145 oligomers were tested for immunogenicity in rabbits, and purified dimers, trimers, and larger multimers elicited similar levels of cross-subtype binding and neutralizing antibodies to tier 1 and some tier 2 viruses. Immunized rabbit sera did not neutralize the highly resistant CO6980v0c22 pseudovirus but did inhibit the homologous infectious molecular clone in a peripheral blood mononuclear cell (PBMC) assay. This Env is currently in good manufacturing practice (GMP) production to be made available for use as a clinical research tool and further evaluation as a candidate vaccine.
  
  
  OBJECTIVE
  At present, the product pipeline for HIV vaccines is insufficient and is limited by inadequate capacity to produce large quantities of vaccine to standards required for human clinical trials. Such products are required to evaluate critical questions of vaccine formulation, route, dosing, and schedule, as well as to establish vaccine efficacy. The gp145 Env protein presented in this study forms physical trimers, binds to many of the well-characterized broad neutralizing MAbs that target conserved Env epitopes, and induce cross-subtype neutralizing antibodies as measured in both cell line and primary cell assays. This subtype C Env gp145 protein is currently undergoing good manufacturing practice production for use as a reagent for preclinical studies and for human clinical research. This product will serve as a reagent for comparative studies and may represent a next-generation candidate HIV immunogen.
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Wieczorek
authors.affiliation: Military HIV Research Program, Bethesda, 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: Advanced Biosciences Laboratories, Inc., Rockville, Maryland, USA.
authors.forename: Vaniambadi
authors.initials: V
authors.lastname: Kalyanaraman
authors.affiliation: Advanced Biosciences Laboratories, Inc., Rockville, Maryland, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Whitney
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Sodsai
authors.initials: S
authors.lastname: Tovanabutra
authors.affiliation: University of California, Davis, California, USA.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Moscoso
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Sanders-Buell
authors.affiliation: New York University School of Medicine and Veterans Affairs Medical Center, New York, New York, USA.
authors.forename: Constance
authors.initials: C
authors.lastname: Williams
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Slike
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Molnar
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dussupt
authors.affiliation: Duke University, Durham, North Carolina, USA.
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Agnes-Laurence
authors.initials: AL
authors.lastname: Chenine
authors.affiliation: HJF-DAIDS, Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Tong
authors.affiliation: HJF-DAIDS, Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Edgar L
authors.initials: EL
authors.lastname: Hill
authors.affiliation: Duke University, Durham, North Carolina, USA.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Klinikum of the University of Munich, Department of Infectious Diseases and Tropical Medicine, Munich, Germany German Center for Infection Research (DZIF), Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
authors.affiliation: National Institute for Medical Research-Mbeya Medical Research Center, Mbeya, Tanzania.
authors.forename: Leonard
authors.initials: L
authors.lastname: Maboko
authors.affiliation: New York University School of Medicine and Veterans Affairs Medical Center, New York, New York, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.affiliation: Duke University, Durham, North Carolina, USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Division of AIDS, NIH, Bethesda, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Pensiero
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Francine
authors.initials: F
authors.lastname: McCutchan
authors.affiliation: University of California, Davis, California, USA.
authors.forename: Shawyon
authors.initials: S
authors.lastname: Malek-Salehi
authors.affiliation: University of California, Davis, California, USA.
authors.forename: R Holland
authors.initials: RH
authors.lastname: Cheng
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.affiliation: Advanced Biosciences Laboratories, Inc., Rockville, Maryland, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: VanCott
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Division of AIDS, NIH, Bethesda, Maryland, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Marovich
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Alving
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Matyas
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Mangala
authors.initials: M
authors.lastname: Rao
authors.affiliation: Military HIV Research Program, Bethesda, Maryland, USA Walter Reed Army Institute of Research, Silver Spring, Maryland, USA vpolonis@hivresearch.org.
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Polonis
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000818:Animals; D004353:Drug Evaluation, Preclinical; D015483:HIV Antibodies / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011817:Rabbits; D014611:Vaccination; D054299:env Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus