Interferon-β expressed by a rabies virus-based HIV-1 vaccine vector serves as a molecular adjuvant and decreases pathogenicity

Abstract

Type I interferon is important in anti-viral responses and in coordinating the innate immune response. Here we explore the use of interferon-β to adjuvant the response to a rabies virus (RV) vaccine vector expressing both HIV-1 Gag and IFN-β. Viral load and immune responses of immunized mice were analyzed over time. Our results indicate that the RV expressing IFN-β (IFN(+)) is highly attenuated when compared to control RV and demonstrate that the expression of IFN-β reduces viral replication approximately 100-fold. Despite the decrease in replication, those mice immunized with the IFN(+) RV had a significantly greater number of activated CD8+ T cells. The increased activation of CD8+ T cells was dependent on IFN-β signaling, as we saw no difference following infection of IFNAR−/− mice. Although mice immunized with IFN(+) have a greater primary immune response than controls, immunized mice that were challenged with vaccinia expressing Gag had no significant difference in the number or functionality of CD8+ T cells. The increased CD8+ T cell activation in the presence of IFN-β, even with greatly reduced viral replication, indicates the beneficial effect of IFN-β for the host.

Rabies Virus Is Recognized by the NLRP3 Inflammasome and Activates Interleukin-1β Release in Murine Dendritic Cells

“…SPBN, a RABV vaccine strain-based vector, has been described previously (27). Vesicular stomatitis virus expressing green fluorescent protein (VSV-GFP) was obtained from John Hiscott (McGill University) (17). For pathogenicity studies, recombinant BNSP-Cre was used (28).…”

“…Supernatants were assessed for the ability to inhibit vesicular stomatitis virus (VSV) replication. Cell culture supernatants were analyzed for type I IFN as described previously (17). Briefly, supernatant collected at 48 h postinfection as described above was UV inactivated.…”

“…Rabies virus (RABV) is a negative-sense single-stranded RNA virus that replicates exclusively in the cytosol (17). Previous reports have shown that RABV RNA is recognized by RIG-I and MDA5, which exclusively signal via IPS-1/MAVS/VISA/Cardif to activate both NF-B-and type I IFN-regulated responses (18)(19)(20).…”

Characterization of a Single-Cycle Rabies Virus-Based Vaccine Vector

“…Recombinant RV was recovered as previously described (15) with the following modifications for single-cycle RV recovery. Briefly, BSR cells were transfected using FuGENE 6 (Roche Diagnostics) with 5 g of pSPBN-⌬G-Gag cDNA, 1.5 g of T7, 2.5 g of pTIT-N, 1.25 g of pTIT-P, 1.25 g of pTIT-L, and 1 g of pTIT-G (per six-well plate).…”

Is Vaccination an Option for Treating Rabies?

“…Since this time the approach has been developed by a number of laboratories in Europe and the United States in pursuit of improved understanding of the biology of the virus and the development of attenuated viruses for use as vaccine candidates [6,7]. One popular approach has been to introduce mammalian innate immune response genes into the rabies virus genome, usually between the glycoprotein gene and the L polymerase gene [8][9][10]. The effect of these introductions when tested in a murine model attenuates the virus through overstimulation of the innate immune response, preventing infection of the central nervous system.…”