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

职业目标：布伦南博士的长期职业目标是在一所大学获得教职，这将利用他作为兽医和科学家的培训，他可以专注于利用动物模型进行发病机制的研究。短期的职业目标包括加强他在实验动物医学和病理学方面的知识，并在基本病毒学方面打下坚实的基础，这样他就可以从宿主和病原体的角度来解释发现。职业发展规划：他将通过参加期刊俱乐部、实验室会议、研讨会和务虚会以及提交研究文章来发展他的沟通技巧。他还将参加科学会议并展示研究成果，这些会议也将使他接触到超出其项目范围的研究领域。通过为本部门制定替代提案，将获得进一步的拨款撰写经验。他将参加实验动物医学培训讲座，以加强他在实验动物医学和病理学方面的基础，并参加由大学提供的研究生生物伦理学讲座，以确保在负责任的研究行为方面打下坚实的基础。研究项目：HIV-2占世界艾滋病病例的5%。我们将HIV-2/EHO在猕猴体内传代，分离并克隆了一种致病病毒HIV-2/304。我们的长期目标是确定猕猴体内HIV-2/304宿主适应的分子和遗传决定因素。我们假设猕猴中的HIV-2/304表型是由于在连续传代过程中积累的突变，这些突变增加了病毒的效率和/或逃避了限制因子。本提案将侧重于定义导致致病表型的hiv /304基因。具体目的是：1)确定与HIV-2/304相比HIV-2/EHO复制周期的阻滞，2)确定TRIM5- α对HIV-2/EHO的影响，以及3)确定嵌合病毒对HIV-2/304宿主适应的遗传决定因素。

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.