The major goal of this co-ordinated, multidisciplinary program is to test the in vivo efficacy of novel immunogens/vaccines in two animal models prior to their evaluation in man. These immunogens would be derived from the following: combinations of T-cell and B-cell epitopes of HIV presented in oligomeric configurations, similar epitopes expressed in a human rhinovirus vector (either as inactivated chimeric viruses or as live virus) and non-replicative or non-cytopathic HIV mutants. As animal models, we have chosen ones in which HIV would be not only infectious but also pathogenic: the Hu-PBL-SCID mouse (with HIV-1 and HIV-2) as a small animal model and the pig-tailed macaque (with HIV-2) as a non-human primate model. Molecularly cloned viruses will be used for homologous or heterologous challenge of immunized animals to minimize the problem of virus heterogeneity in the initial evaluation. The pathogenic parameter is also important since a successful vaccine may protect against disease but not infection. Furthermore, the potential use of vaccines as therapeutic agents can be evaluated in these models.
The specific aims of this co- operative grant proposal are: (1) To develop infection and disease models with molecularly cloned viruses of HIV-1 and HIV-2. Hu-PBL-SCID mice will be infected with HIV-1 or HIV-2, while pig-tailed macaques will be infected with HIV-2. Mutants of HIV-2 with increases virulence will be constructed to facilitate disease development in the macaque model. (2) To use the synthetic peptide and gene approaches to present HIV peptide epitope in oligomeric configurations. To combine T-cell and B-cell epitopes in chimeric peptides with appropriate adjuvants for immunization. (3) To use human rhinovirus 14 as a live vector and as a protein expression vector for presentation of HIV-1 and HIV-2 epitopes. (4) To generate non-replicative and/or non-cytopathic HIV mutants as a source of inactivated or attenuated live vaccines. (5) To generate neutralizing antibodies against material from (2) to (4) for passive administration into Hu-PBL-SCID mice prior to or after HIV infection. The SCID mouse model can also be used to determine the potential efficacy of defective """"""""interfering"""""""" particles of HIV for therapy. (6) To immunize naive or HIV-2 infected pig-tailed macaques with immunogens derived from 2) to 4) followed by molecular, immunological, and clinical monitoring and challenge experiments if appropriate. This program involves close intellectual and scientific collaborations among five institutions. We believe this consortium will provide the right combination of talent, facilities, expertise, and novel approaches to facilitate the design and refinement of an AIDS vaccine.
Showing the most recent 10 out of 25 publications
