Determinants of host adaptation in a Macaca nemestrina-adapted HIV-2 isolate

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DESCRIPTION (provided by applicant): Career goals: Dr. Brennan's long-term career goal is to obtain a faculty appointment at a university that will take advantage of his training as a veterinarian and a scientist, who can focus on research utilizing animal models of pathogenesis. Short-term career goals include reinforcing his knowledge of laboratory animal medicine and pathology, and developing a firm foundation in basic virology, so that he can interpret discoveries in terms of both the host and the pathogen. Career development plan: He will develop his communication skills by participation in journal clubs, lab meetings, seminars, and retreats, and through the submission of research articles. He will also attend and present research findings at scientific meetings, and these conferences will also expose him to fields of study beyond the scope of his project. Further grant-writing experience will be gained by developing an alternate proposal for the department. He will attend laboratory animal medicine training lectures to reinforce his foundations in lab animal medicine and pathology, and graduate bioethics lectures offered by the University to ensure a firm foundation in the responsible conduct of research. Research project: HIV-2 is responsible for 5% of the world's AIDS cases. We passaged HIV-2/EHO in Macaca nemestrina, then isolated and molecularly cloned a pathogenic virus, HIV-2/304. Our long-term goal is to define the molecular and genetic determinants of HIV-2/304 host adaptation in macaques. We hypothesize that the HIV-2/304 phenotype in macaques is due to mutations accumulated during serial passage, which increase viral efficiency and/or evade restriction factors. This proposal will focus on the definition of HIV-2/304 genes that contribute to the pathogenic phenotype. The specific aims are to: 1) define blocks to the replication cycle of HIV-2/EHO compared to HIV-2/304, 2) define the effect of TRIM5- alpha on HIV-2/EHO, and 3) define genetic determinants of HIV-2/304 host adaptation using chimeric viruses.