CHIMERIC RHINOVIRUSES AS TOOLS FOR VACCINE DEVELOPMENT AND CHARACTERIZATION OF PROTEIN EPITOPES

Chimeric human rhinoviruses (HRVs) have the potential to serve as vacc ines against a wide variety of diseases. Such vaccines can be develope d optimally by generating libraries of chimeric HRVs displaying immuno gens from dangerous pathogens or tumor cells in many different conform ations. Extremely large numbers of conformationally defined presentati ons of foreign epitopes can be produced efficiently by flanking transp lanted epitopes with linkers, or adapters, of small segments of random ized amino acids. In addition, the individual residues of the immunoge nic sequences can be encoded in proportion to their prevalence in data bases. generating composite immunogens that function as mimotopes. The diversity of sequences and conformations improves the likelihood of g enerating immunologically valuable vaccine candidates. Chimeric viruse s thus generated can be propagated and purified to select for viruses whose growth and physical stability are like those of wild-type HRV. V iruses containing a foreign epitope in antigenically relevant conforma tions can then be captured by immunoselection with neutralizing antibo dies directed against the foreign pathogen. Using this approach. we ha ve been able to generate HRV chimeras that present V3 loop sequences o f the human immunodeficiency virus type 1 (HIV-1) in immunologically r elevant conformations. Antisera directed against such chimeras can neu tralize multiple strains of HIV-1 in cell culture, suggesting that the HRV 14:HIV-1 chimeras may be presenting their V3 loop sequences in ma nners that mimic those of multiple strains of HIV. Immunologically int eresting chimeras can be examined using X-ray crystallography to yield detailed information about the structures of chimeras with immunogeni c epitopes. This information may lead to a greater understanding of ke y functional and structural elements of immunogenicity. The chimeric H RV system allows one to present virtually any protein epitope or mimit ope thereof, identify viruses with immunological characteristics that mimic those of the foreign pathogen, and examine the structures of the se immunogenic sequences at the atomic level.