title: The stem of vesicular stomatitis virus G can be replaced with the HIV-1 Env membrane-proximal external region without loss of G function or membrane-proximal external region antigenic properties.
abstract: The structure of the HIV-1 envelope membrane-proximal external region (MPER) is influenced by its association with the lipid bilayer on the surface of virus particles and infected cells. To develop a replicating vaccine vector displaying MPER sequences in association with membrane, Env epitopes recognized by the broadly neutralizing antibodies 2F5, 4E10, or both were grafted into the membrane-proximal stem region of the vesicular stomatitis virus (VSV) glycoprotein (G). VSV encoding functional G-MPER chimeras based on G from the Indiana or New Jersey serotype propagated efficiently, although grafting of both epitopes (G-2F5-4E10) modestly reduced replication and resulted in the acquisition of one to two adaptive mutations in the grafted MPER sequence. Monoclonal antibodies 2F5 and 4E10 efficiently neutralized VSV G-MPER vectors and bound to virus particles in solution, indicating that the epitopes were accessible in the preattachment form of the G-MPER chimeras. Overall, our results showed that the HIV Env MPER could functionally substitute for the VSV G-stem region implying that both perform similar functions even though they are from unrelated viruses. Furthermore, we found that the MPER sequence grafts induced low but detectable MPER-specific antibody responses in rabbits vaccinated with live VSV, although additional vector and immunogen modifications or use of a heterologous prime-boost vaccination regimen will be required to increase the magnitude of the immune response.
authors.affiliation: 1 The International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory , Brooklyn, New York.
authors.forename: Ivo C
authors.initials: IC
authors.lastname: Lorenz
authors.forename: Hanh T
authors.initials: HT
authors.lastname: Nguyen
authors.forename: Marina
authors.initials: M
authors.lastname: Kemelman
authors.forename: Ross W
authors.initials: RW
authors.lastname: Lindsay
authors.forename: Maoli
authors.initials: M
authors.lastname: Yuan
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wright
authors.forename: Heather
authors.initials: H
authors.lastname: Arendt
authors.forename: Jaap Willem
authors.initials: JW
authors.lastname: Back
authors.forename: Joanne
authors.initials: J
authors.lastname: DeStefano
authors.forename: Simon
authors.initials: S
authors.lastname: Hoffenberg
authors.forename: Gavin
authors.initials: G
authors.lastname: Morrow
authors.forename: Christy K
authors.initials: CK
authors.lastname: Jurgens
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Phogat
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Zamb
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Parks
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D011817:Rabbits; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018116:Vesiculovirus / Q000235:genetics / Q000254:growth & development / Q000276:immunology / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D014779:Virus Replication; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; C028391:G protein, vesicular stomatitis virus; D015483:HIV Antibodies; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins; D054299:env Gene Products, Human Immunodeficiency Virus