This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This project is part of a large consortium on AIDS vaccine development sponsored by the Gates Foundation and the International AIDS Vaccine Initiative (IAVI). A major goal of the consortium is to develop new approaches to AIDS vaccine using the rhesus macaque model to assess efficacy and in particular compare efficacy of all approaches in an identical challenge protocol. The specific goal of this project is to design, construct and test gene-deleted RhCMV vectors that have been optimized for immunogenicity and safety, and then comparatively assess both wildtype RhCMV vectors and gene-deleted RhCMV vectors in the standard efficacy protocol developed for the entire consortium. RhCMV vectors will be tested alone as well as in heterologous prime-boost protocols using adenovirus and adeno-associated viral (AAV) vectors as the heterologous prime or boost. Thus this project will have 3 'Activities'. In Activity #1 ('CMV Vector Design and Development'), we will 1) construct and evaluate RhCMV mutants that lack one or more 'non-essential' host modulation/immune evasion genes, 2) design and construct expression inserts (and vectors) capable of simultaneous expression of multiple SIV genes and 'safety' inserts that will allow in vivo control of vector replication with administration of an external drug (e.g., vectors whose growth is either dependent on or terminated by a drug of high bioavailability such as doxycycline), 3) provide virologic and pathologic assessment of RhCMV vector infections in the monkeys administered these vectors as part of the first or second efficacy trials (see below), and 4) develop and construct an attenuated/modified mutant of human cytomegalovirus (HCMV) analogous to the optimal RhCMV design. In Activity #2, we will assess the immunogenicity, pathobiology and protective efficacy of 'wildtype' RhCMV vectors, with or without Adenovirus (Ad) 5 Boosting. In Activity #3, we will assess the immunogenicity, pathobiology and protective efficacy of attenuated (gene-modified or gene-deleted) RhCMV vectors, with or without AAV priming.
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