Effect of Statins on HIV-1 Biology

描述(由申请人提供)：克雷格·弗莱彻博士是一名兽医，正在参加实验动物医学的结构化博士后奖学金计划，并将通过比较医学临床培训和正式博士培训的独特整合来继续扩展他的科学技能。这个指导临床科学家发展奖的目的是支持细胞免疫学和逆转录病毒发病机制的研究计划，该计划将最终获得博士学位和继续研究经验的机会。弗莱彻博士的长期目标是成为一名首席研究员，利用动物模型研究艾滋病毒的发病机制和治疗方法。首席研究员的科学培训将在约翰·霍普金斯大学的白细胞免疫化学实验室进行，由赞助商詹姆斯·E·K·希尔德雷思博士指导。候选人的培训计划包括应用于艾滋病动物模型的现代分子技术和研究方法的实验室和教学培训。 希尔德雷思实验室首席研究员进行的初步工作表明，他汀类药物(洛伐他汀)在体外可以抑制HIV-1和SIV的感染和复制。该研究设计旨在了解整合素和脂筏在体外HIV和SIV生物学中发挥作用的机制。三个特定的目标是：(1)确定他汀类药物是否影响脂筏的形成，从而改变整合素(和其他细胞蛋白)对HIV-1病毒粒子的掺入；(2)确定他汀类药物对整合素和趋化因子受体功能的调节在体外对HIV的出芽、进入和病毒诱导的趋化作用的影响；(3)确定他汀类药物是否通过诱导细胞凋亡来抑制HIV和SIV在PBMC培养中的传播。他汀类药物是现有的最有效的降胆固醇药物之一，在世界各地被广泛开出处方。高脂血症和高胆固醇血症是接受抗逆转录病毒治疗的HIV感染患者的普遍情况。除了该药物家族对胆固醇合成的影响外，研究人员最近还发现，他汀类药物直接抑制主要的a2整合素LFA-1。鉴于他汀类药物的这种双重作用，以及LFA-1和脂筏在HIV-1生物学中的重要作用，这些化合物可能是治疗和研究艾滋病的重要工具。约翰霍普金斯大学比较医学系为兽医科学家的培训提供了理想的环境，并最大限度地发挥了首席研究员建立强大研究基础并发展成为独立研究员的潜力。

DESCRIPTION (provided by applicant): Dr. Craig Fletcher, a veterinarian, is in a structured postdoctoral fellowship program in Laboratory Animal Medicine and will continue to expand upon his scientific skills through unique integration of clinical training in comparative medicine and formal doctoral training. The purpose of this Mentored Clinical Scientist Development Award is to support a research program in cellular immunology and retroviral pathogenesis, which will culminate in both the Ph.D. degree and the opportunity for continued research experience. Dr. Fletcher's long-term goal is to become a principal investigator employing animal models to investigate the pathogenesis and therapy of HIV. The principal investigator's scientific training will be conducted in the Leukocyte Immunochemistry Laboratory at Johns Hopkins University, under the guidance of the sponsor Dr. James E. K. Hildreth. The candidate's training plan includes laboratory and didactic training in contemporary molecular techniques and research methods, applied to an animal model of AIDS. Preliminary work conducted by the principal investigator in the Hildreth's laboratory suggests that statins (lovastatin) inhibit HIV-1 and SIV infection and replication in vitro. The study design is aimed at understanding the mechanisms by which integrins and lipid rafts play a role in HIV and SIV biology in vitro. The three specific aims to be addressed are: (1) to determine if statins affect lipid raft formation thus alter the incorporation of integrins (and other cellular proteins) into HIV-1 virions; (2) to determine the impact of statin modulation of integrin and chemokine receptor function on HIV budding, entry, and virus-induced chemotaxis in vitro; (3) to determine if statins inhibit the spread of HIV and SIV in PBMC cultures by inducing apoptosis. Statins are among the most powerful cholesterol lowering drugs available and are widely prescribed around the world. Dyslipidemia and hypercholesteremia are prevalent conditions in patients with HIV infection on anti-retroviral therapy. In addition to this drug family's effect on cholesterol synthesis, investigators have recently found that statins directly inhibit the major a2 integrin, LFA-1. Given this dual effect of statins and the important role of LFA-1 and lipid rafts in the biology of HIV-1, these compounds represent a potentially important therapeutic and investigative tool for AIDS. The Department of Comparative Medicine of the Johns Hopkins University provides an ideal setting for training veterinarian-scientists and maximizes the potential for the principal investigator to establish a strong research foundation and develop into an independent investigator.