title: Comparative Immunogenicity of Evolved V1V2-Deleted HIV-1 Envelope Glycoprotein Trimers.
abstract: Despite almost 30 years of research, no effective vaccine has yet been developed against HIV-1. Probably such a vaccine would need to induce both an effective T cell and antibody response. Any vaccine component focused on inducing humoral immunity requires the HIV-1 envelope (Env) glycoprotein complex as it is the only viral protein exposed on the virion surface. HIV-1 has evolved several mechanisms to evade broadly reactive neutralizing antibodies. One such a mechanism involves variable loop domains, which are highly flexible structures that shield the underlying conserved epitopes. We hypothesized that removal of such loops would increase the exposure and immunogenicity of these conserved regions. Env variable loop deletion however often leads to protein misfolding and aggregation because hydrophobic patches becoming solvent accessible. We have therefore previously used virus evolution to acquire functional Env proteins lacking the V1V2 loop. We then expressed them in soluble (uncleaved) gp140 forms. Three mutants were found to perform optimally in terms of protein expression, stability, trimerization and folding. In this study, we characterized the immune responses to these antigens in rabbits. The V1V2 deletion mutant ΔV1V2.9.VK induced a prominent response directed to epitopes that are not fully available on the other Env proteins tested but that effectively bound and neutralized the ΔV1V2 Env virus. This Env variant also induced more efficient neutralization of the tier 1 virus SF162. The immune refocusing effect was lost after booster immunization with a full-length gp140 protein with intact V1V2 loops. Collectively, this result suggests that deletion of variable domains could alter the specificity of the humoral immune response, but did not result in broad neutralization of neutralization-resistant virus isolates.
authors.affiliation: Department of Medical Microbiology, Laboratory of Experimental Virology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ilja
authors.initials: I
authors.lastname: Bontjer
authors.forename: Mark
authors.initials: M
authors.lastname: Melchers
authors.forename: Tommy
authors.initials: T
authors.lastname: Tong
authors.forename: Thijs
authors.initials: T
authors.lastname: van Montfort
authors.forename: Dirk
authors.initials: D
authors.lastname: Eggink
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.forename: William C
authors.initials: WC
authors.lastname: Olson
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: James M
authors.initials: JM
authors.lastname: Binley
authors.forename: Ben
authors.initials: B
authors.lastname: Berkhout
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D000917:Antibody Formation / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D009500:Neutralization Tests; D011817:Rabbits; D017384:Sequence Deletion; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus