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

简介(由申请人提供)：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员职位，该大学将利用他作为兽医和科学家的培训，专注于利用动物发病模型进行研究。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，并在基础病毒学方面奠定坚实的基础，这样他就可以从宿主和病原体的角度解释发现。职业发展计划：他将通过参加期刊俱乐部、实验室会议、研讨会和务虚会，以及通过提交研究论文来发展他的沟通技能。他还将出席科学会议并发表研究成果，这些会议还将使他接触到项目范围以外的研究领域。通过为该部制定备选方案，将获得更多的赠款编写经验。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工作中奠定坚实的基础。研究项目：HIV-2占全球艾滋病病例的5%。将HIV-2/EHO在恒河猴体内传代，分离并分子克隆了一株致病病毒HIV-2/304。我们的长期目标是确定HIV-2/304宿主在猕猴体内适应的分子和遗传决定因素。我们推测，猕猴的HIV-2/304表型是由于在连续传代过程中积累的突变导致的，这些突变增加了病毒效率和/或避开了限制因子。这项建议将侧重于HIV-2/304基因的定义，这些基因对致病表型有贡献。其具体目的是：1)确定HIV-2/EHO与HIV-2/304相比的复制周期的障碍，2)定义TRIM5-α对HIV-2/EHO的影响，以及3)使用嵌合病毒确定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.