The applicants have developed a method of genetically engineering virulence attenuated strains of positive stranded viruses. Through this method, it is possible to create replication competent recombinant viruses that stably carry and express genetic sequences derived from other pathogenic agents. The objective of this proposal is to evaluate the potential of recombinant Yellow Fever Virus expressing Env, Gag and Nef proteins derived from primary isolates of the human immunodeficiency virus (HIV) to serve as safe and effective vaccines for the prevention of infection by these immunosuppressive lentiviruses. Important advantages of the live-attenuated Yellow Fever vaccine include its ability to induce long-lasting immunity, its safety, affordability and documented efficacy in both developed and developing nations. In these studies, recombinant live-attenuated (strain 17D) YFV will be constructed to express HIV envelope, Gag and Nef. The expression of HIV envelope and its structure will be studied. Yellow fever recombinants will be optimized for replication competence and genetic stability. YFV recombinants will be used to inoculate mice and their ability to elicit neutralizing antibodies to primary isolates will be evaluated. Because YFV is an enveloped virus it is likely that glycoproteins like HIV envelope would be readily expressed and the native structure of envelope proteins preserved. The applicant's approach to express the HIV envelope may also result in the incorporation of HIV envelope in the YFV particle, thus this approach may generate HIV pseudovirions-like particles. In addition, because YFV recombinants derived from the approach are replication competent viruses, these vaccine vector systems may facilitate expression and presentation to the immune system of native Env, Gag and Nef in vivo.
| McAllister, A; Arbetman, A E; Mandl, S et al. (2000) Recombinant yellow fever viruses are effective therapeutic vaccines for treatment of murine experimental solid tumors and pulmonary metastases. J Virol 74:9197-205 |
