The long term goal of this project is to develop recombinants of the enveloped virus, vesicular stomatitis virus (VSV), as an HIV vaccine. This laboratory has developed a system for obtaining recombinants of this negative-strand RNA virus that express either the HIV-1 envelope protein or a hybrid protein consisting of the extracellular and transmembrane domains of the HIV-1 envelope linked to the cytoplasmic domain of the VSV glycoprotein (G). Several important features of the recombinant VSV system make it useful for vaccine development: VSV recombinants can be grown to extremely high titers, the recombinants are genetically stable and express large amounts of the foreign protein with only five other viral proteins, the HIV/G hybrid protein is incorporated into the virus particle, and the recombinants can be tested for antigenicity in a small animal model. VSV causes a non-lethal, self-limiting disease in livestock, but it causes only a mild, flu-like illness in humans. It may therefore be possible to use attenuated, live VSV/HIV recombinants directly as human vaccines. Replication-defective or killed VSV/HIV recombinants could also be used as a completely safe alternative. The immediate goals of this optimize incorporation of a recombinant HIV-1 envelope into VSV/HIV particles in the absence of the VSV envelope protein, to construct VSV/HIV recombinants expressing the envelope of a primary HIV-1 isolate, to generate defective HIV/VSV recombinants that are capable of only one round of infection, and to test the live, defective, or killed VSV/HIV recombinants for their ability to induce HIV-1 neutralizing antibodies in mice.
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