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

Brennan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，他们可以专注于利用发病机制的动物模型进行研究。短期职业目标包括加强他对实验室动物医学和病理学的了解，并在基础病毒学方面打下坚实的基础，以便他能够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提交研究文章来发展自己的沟通技巧。他还将出席并在科学会议上介绍研究成果，这些会议也将使他接触到超出其项目范围的研究领域。进一步的赠款写作经验将通过开发部门的替代提案获得。他将参加实验室动物医学培训讲座，以加强他在实验室动物医学和病理学的基础，并由大学提供的研究生生物伦理讲座，以确保在负责任的研究行为的坚实基础。研究项目：HIV-2占世界艾滋病病例的5%。我们在猕猴中传代HIV-2/EHO，然后分离并分子克隆了致病病毒HIV-2/304。我们的长期目标是确定猕猴中HIV-2/304宿主适应性的分子和遗传决定因素。我们假设猕猴中的HIV-2/304表型是由于连续传代过程中积累的突变，这增加了病毒效率和/或逃避限制因子。该提案将侧重于定义导致致病表型的HIV-2/304基因。具体目标是：1）定义与HIV-2/304相比HIV-2/EHO复制周期的阻断，2）定义TRIM 5-α对HIV-2/EHO的影响，3）使用嵌合病毒定义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.