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191 Designing Whole-Killed Virus Vaccines
E. Chertova*, J. W. Bess, Jr., J. M. Hilburn, T. M. Schaden, R. C. Sowder II, J. Lifson, L. O. Arthur, and L. E. Henderson
AIDS Vaccine Program, SAIC Frederick, MD, US
Native presentation of the viral envelope (Env) antigens, gp120 (SU), and transmembrane (TM) protein are important in the vaccine strategies. Our program has focused on the design and synthesis of whole inactivated virion particle vaccines, specifically, using methods to irreversibly inactivate live virus while retaining native and functional envelope (Env) proteins (gp120 bound to transmembrane protein (TM) in native trimeric structures) since these structures are required to elicit neutralizing responses. To determine the contribution of SU density to the efficacy of the vaccine we focus on viral incorporation and retention of Env proteins.
We have shown that mild oxidizing agents such as Aldrithiol-2 can totally inactivate HIV and SIV without modification of surface proteins. Thus, viruses inactivated by this method still retain native and functional surface proteins, including gp120, TM, and HLA class I and class II. Whole virus inactivated by this procedure has been tested as an immunogen and found to elicit a protective effect in immunized monkeys. As an extension of this strategy we are developing methods to vary the amounts of functional Env on the surface of the inactivated virion particles. Physical parameters that contribute to the average surface density of Env complexes on purified virus and AT-2 inactivated particle preparations have been explored. These include temperature and freeze-thaw cycles. Heat treatment of viral particles has been shown to strip gp120 from virion surface with preserving TM protein, which helped us to make a viral particle with low density of SU. Currently we have AT-2 inactivated virus prepared from biologically and molecularly cloned SIVs with high and low surface densities of Env complexes. We are preparing to test these high and low Env density immunogens for their protective immunological responses in SIV/macaque model systems using homologous and heterologous challenges with pathogenic strains of SIV. These tests will be conducted with both the SIVMne and SIVMac macaque models.
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