title: A Bivalent, Chimeric Rabies Virus Expressing Simian Immunodeficiency Virus Envelope Induces Multifunctional Antibody Responses.
abstract: We previously showed that a matrix (M) gene-deleted rabies virus (RABV)-based vaccine (RABV-ΔM) is highly immunogenic and induces potent B cell responses in the context of RABV infection. We speculated that RABV-ΔM expressing HIV proteins would also induce potent B cell responses against HIV antigens. As a prerequisite to future studies in nonhuman primates, we completed immunogenicity studies in mice to confirm the ability of RABV-ΔM to induce polyfunctional B cell responses in the context of HIV. To that end, the envelope protein from the mac239 strain of SIV (SIVmac239Env) was cloned into RABV-ΔM, resulting in RABV-ΔM-Env. Infectious virus was recovered following standard methods and propagated on baby hamster kidney cells stably expressing RABV M [>10(7) focus forming units (ffu)/ml]. Western blot analysis of cell lysates or of purified virions confirmed Env expression on the surface of infected cells and within virus particles, respectively. Positive neutralization activity against a neutralization-sensitive SIV strain and to a lesser extent against a neutralization-resistant SIV strain was detected in mice after a single intramuscular inoculation with RABV-ΔM-Env. The quality, but not quantity, of the antibody response was enhanced via boosting with recombinant gp130 or RABV-ΔM-Env as measured by an increase in antibody avidity and a skewing toward a Th1-type antibody response. We also show that an intradermal inoculation induces higher antibodies than an intramuscular or intranasal inoculation. An intradermal inoculation of RABV-ΔM-Env followed by a boost inoculation with recombinant gp130 produced anti-SIV antibodies with neutralizing and nonneutralizing antibody (nNAb) effector functions. Together, RABV-ΔM-Env induces B cells to secrete antibodies against SIV with the potential to clear both "free" and cell-associated virus. Strategies capable of eliciting both NAbs as well as nNAbs might help to improve the efficacy of HIV-1 vaccines.
authors.affiliation: 1 Department of Microbiology and Immunology, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Amber
authors.initials: A
authors.lastname: Dunkel
authors.affiliation: 1 Department of Microbiology and Immunology, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Shixue
authors.initials: S
authors.lastname: Shen
authors.affiliation: 2 Department of Surgery, Duke University , Durham, North Carolina.
authors.forename: Celia C
authors.initials: CC
authors.lastname: LaBranche
authors.affiliation: 2 Department of Surgery, Duke University , Durham, North Carolina.
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.affiliation: 1 Department of Microbiology and Immunology, Thomas Jefferson University , Philadelphia, Pennsylvania.|3 Jefferson Vaccine Center, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: James P
authors.initials: JP
authors.lastname: McGettigan
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D007271:Injections, Intradermal; D007273:Injections, Intramuscular; D008810:Mice, Inbred C57BL; D011819:Rabies Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D011820:Rabies virus / Q000235:genetics / Q000276:immunology*; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D011819:Rabies Vaccines; D018449:SAIDS Vaccines
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