SALMONELLA-HIV CHIMERA AS VACCINE

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The long-term objective of the research is to construct strains of Salmonella which produce antigens of HIV for use as live vaccine, given by mouth, to humans, in the expectation that delivery of HIV antigens in this way will evoke strong immune responses, both humoral and cellular to the "passenger" HIV antigen(s) and with the hope that such responses will serve not only to prevent infection if administered to uninfected subjects but perhaps also to arrest progression from silent infection to AIDS if given to symptom-free antibody positive subjects. The bacterial carriers for immunization of laboratory animals are S. typhimurium and S. dublin strains with non-reverting mutations at aroA, blocking aromatic biosynthesis and causing requirement for p-aminobenzoic acid, not available in host tissues; these strains are safe and effective as live vaccines, parenteral or oral, for protection of animals against systemic salmonella infections and are effective presenters of cloned antigen genes from other organisms, e.g. the M protein of Streptococcus pyogenes. They will be given constructed plasmids which include HIV DNA sequences for production of HIV antigens, either as proteins or fusion proteins or as exposed amino acid sequences in the flagellin of host flagella. Plasmids from E. coli strains expressing HIV antigens will be transferred to S. typhimurium or S. dublin live-vaccine strains for test of expression and stability, in vitro and in vivo, and for ability to evoke HIV immune responses in laboratory animals. Plasmids evoking good responses will be transferred to available S. typhi candidate live-vaccine strains, such as 541Ty and 543Ty, made non-virulent by deletion mutation at aroA and at purA (causing adenine requirement) which caused no adverse effects when fed to volunteers and evoked cellular immune responses in all such volunteers. If the S. typhi live-vaccine strains given the constructed plasmids appear satisfactory in respect of expression of HIV epitopes and of stability they will be made available for testing elsewhere, in volunteers.