TRAINING IN MOLECULAR VIROLOGY AND AIDS PATHOGENESIS

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A training program for Dr. Anne Lewis is described in this Physician Scientist Award (K11) application. The program is designed to provide Dr. Lewis with the skills to investigate viral pathogenesis at a molecular level in order for her to ultimately become an independent investigator. Dr. Lewis is a board certified veterinary pathologist who has recently returned to graduate school to pursue a Ph.D. degree in Experimental Pathology in the Department of Veterinary Pathobiology at the Ohio State University. She is co-sponsored by Dr. Philip Johnson and Dr. Paul Stromberg. The specific aims of Phase I of the training program for Dr. Lewis are: (i) to obtain basic training in virology, tissue culture and molecular biology, and (ii) to apply these skills in the construction of a series of molecular chimeras between SIV and HIV-1. Basic training will be accomplished through pertinent didactic coursework, participation in specialized courses covering such topics as advanced in situ hybridization, active benchwork in the laboratory, and regular consultation and interaction with her co-sponsors. The goal of the research proposed for Phase I is the development of a model of HIV-1 infection in non-human primates using SIV/HlV-1 molecular chimera. During the pre-Phase I portion of her training, Dr. Lewis has successfully constructed an SIV/HlV-1 prototype chimera (SHIV) composed of a background SIV with high replicative ability in which the envelope gene is provided by HIV-1. In vitro viability and infectivity for pig-tailed macaques has been demonstrated. The goal of the construction of further chimeras in Phase I is to increase the replicative ability of the chimera by restoring the HIV-1 vpu open reading frame and restoring the SIV tat reading frame and the associated splice junction. Phase I will last 2 years. Completion of Phase I will be determined by completion of Phase I research as described above as well as the successful completion of the requirements for the Ph.D. degree as decreed by the Ohio State University. The specific aims for Phase II research are: (i) to construct SHIV chimeras with divergent HIV-1 envelope genes; (ii) to construct SHIV chimeras with an HIV-1 reverse transcriptase; and (iii) to test additional SHIV chimeras in the pig-tailed macaque model. Phase II is an expansion of skills and ideas developed during Phase I and will last 2 years.