Live, attenuated virus strains are the most effective AIDS vaccines identified to date. The protective immune responses elicited by attenuated vaccines are unknown. We recently developed a monkey model in which immune cells can transferred between animals, allowing us to explore the immunological requirements for vaccine-mediated protection. Similar adoptive transfer experiments in mice have revolutionized our understanding of pathogen immunity but have been impossible to perform in monkeys. In this proposal, we test the hypothesis that lymphocytes from animals vaccinated with attenuated viruses are responsible for the success of attenuated vaccines. We will test this hypothesis by transferring variable numbers of lymphocytes from monkeys vaccinated with live, attenuated virus into vaccine naive recipients who will subsequently be infected with pathogenic virus. We anticipate that a dose-dependent relationship exists between the number of transferred lymphocytes and protection from pathogenic disease. If we find that a high dose (1 x 1010) total lymphocytes are protective, we will test progressively lower lymphocyte doses to determine the protective threshold. If high doses of transferred lymphocytes are not protective, we will attempt to augment protection by combining lymphocyte transfer with transfer of antibodies purified from attenuated vaccinees. Successful completion of these experiments will determine which immune responses are responsible attenuated-vaccine mediated protection, one of the most important questions in contemporary AIDS vaccine research. Moreover, demonstration that adoptive transfer studies are feasible in macaques will potentiate future studies examining the minimal immunological prerequisites for vaccine-mediated protection.
With the number of new infections rising faster than ever, a prophylactic vaccine for HIV is urgently needed. Live strains of virus, genetically modified to grow poorly, elicit the most effective immune responses ever witnessed in more than 20 years of testing. For the first time, we will attempt to transfer this immunity between animals in order to understand which arms of the immune response are involved in protection.
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