title: A comparative immunogenicity study of HIV-1 virus-like particles bearing various forms of envelope proteins, particles bearing no envelope and soluble monomeric gp120.
abstract: To assess the potential of native Envelope glycoprotein (Env) trimers as neutralizing antibody vaccines, we immunized guinea pigs with three types of VLPs and soluble gp120. Particles included "SOS-VLPs" (bearing disulfide-shackled functional trimers), "UNC-VLPs" (bearing uncleaved nonfunctional Env) and "naked VLPs" (bearing no Env). The SOS-VLPs were found to have a density of about 27 native trimers per particle, approximately twice that of live inactivated HIV-1 preparations. As immunogens, UNC- and SOS-VLP rapidly elicited anti-gp120 antibodies focused on the V3 loop and the gp120 coreceptor binding site. Reactivity to the gp41 immunodominant domain was absent in SOS-VLP sera, presumably because gp120-gp41 association is stabilized, effectively covering this epitope. Gp120-immune sera reacted with the receptor binding sites of gp120 and were less focused on the V3 loop. Some Env-VLP sera neutralized primary isolates at modest titers. The measurement of neutralization was found to be affected by the cell lines used. Depending on the assay particulars, non-Env specific antibodies in VLP sera could enhance infection, or nonspecifically neutralize. However, a neutralization assay using TZM-BL cells was essentially clear of these effects. We also describe a native trimer binding assay to confirm neutralization activity in a manner that completely eliminates nonspecific effects. Overall, our data suggests that Env-VLP sera were primarily focused on nonfunctional forms of Env on VLP surfaces, possibly gp120/gp41 monomers and not the trimers. Therefore, to make progress toward a more effective VLP-based vaccine, we will need to find ways to refocus the attention of B cells on native trimers.
authors.affiliation: Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121, USA.
authors.forename: Emma T
authors.initials: ET
authors.lastname: Crooks
authors.forename: Penny L
authors.initials: PL
authors.lastname: Moore
authors.forename: Michael
authors.initials: M
authors.lastname: Franti
authors.forename: Charmagne S
authors.initials: CS
authors.lastname: Cayanan
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.forename: Pengfei
authors.initials: P
authors.lastname: Jiang
authors.forename: Robbert P
authors.initials: RP
authors.lastname: de Vries
authors.forename: Cheryl
authors.initials: C
authors.lastname: Wiley
authors.forename: Irina
authors.initials: I
authors.lastname: Zharkikh
authors.forename: Norbert
authors.initials: N
authors.lastname: Schülke
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Roux
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: James M
authors.initials: JM
authors.lastname: Binley
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D006168:Guinea Pigs; D015483:HIV Antibodies / Q000097:blood; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D009500:Neutralization Tests
chemical_list: D016915:AIDS Vaccines; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41