A Bivalent, Chimeric Rabies Virus Expressing Simian Immunodeficiency Virus Envelope Induces Multifunctional Antibody Responses

作者：Dunkel Amber; Shen Shixue; LaBranche Celia C; Montefiori David; McGettigan James P^*

来源：AIDS Research and Human Retroviruses, 2015, 31(11): 1126-1138.

DOI：10.1089/aid.2014.0319

We previously showed that a matrix (M) gene-deleted rabies virus (RABV)-based vaccine (RABV-Delta M) is highly immunogenic and induces potent B cell responses in the context of RABV infection. We speculated that RABV-Delta M 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-Delta M 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-Delta M, resulting in RABV-Delta M-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-Delta M-Env. The quality, but not quantity, of the antibody response was enhanced via boosting with recombinant gp130 or RABV-Delta M-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-Delta M-Env followed by a boost inoculation with recombinant gp130 produced anti-SIV antibodies with neutralizing and nonneutralizing antibody (nNAb) effector functions. Together, RABV-Delta M-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.

• 出版日期2015-11-1