Effect of Statins on HIV-1 Biology

他汀类药物对 HIV-1 生物学的影响

• 批准号: 6696408
• 负责人: Craig A Fletcher
• 金额: $ 6.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696408
• 关键词: antiviral agents; apoptosis; biological signal transduction; cell adhesion molecules; chemotaxis; clinical research; cytokine receptors; human immunodeficiency virus 1; integrins; lovastatin; membrane lipids; pharmacokinetics; simian immunodeficiency virus; steroid biosynthesis; tissue /cell culture; virus infection mechanism

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.

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博士后研究金项目，并将通过比较医学临床培训和正式博士培训的独特整合，继续扩大他的科学技能。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，这将最终在博士学位。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主要研究者，利用动物模型研究艾滋病毒的发病机制和治疗。主要研究者的科学培训将在申办者Dr. James E.的指导下在约翰霍普金斯大学的白细胞免疫化学实验室进行。K.希尔德雷思候选人的培训计划包括现代分子技术和研究方法的实验室和教学培训，应用于艾滋病的动物模型。 由Hildreth实验室的主要研究者进行的初步工作表明，他汀类药物（洛伐他汀）在体外抑制HIV-1和SIV感染和复制。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。要解决的三个具体目标是：（1）确定他汀类药物是否影响脂筏形成，从而改变整联蛋白的掺入（2）确定他汀类药物调节整联蛋白和趋化因子受体功能对体外HIV出芽、进入和病毒诱导的趋化性的影响;（3）确定他汀类药物是否通过诱导细胞凋亡抑制HIV和SIV在PBMC培养物中的传播。他汀类药物是最强大的降胆固醇药物之一，在世界各地被广泛使用。血脂异常和高脂血症是接受抗逆转录病毒治疗的艾滋病毒感染患者的常见疾病。除了这个药物家族对胆固醇合成的影响外，研究人员最近发现他汀类药物直接抑制主要的α 2整联蛋白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，这些化合物代表了一种潜在的重要的艾滋病治疗和研究工具。约翰霍普金斯大学比较医学系为培训兽医科学家提供了理想的环境，并最大限度地发挥了主要研究者的潜力，以建立强大的研究基础，并发展成为一名独立的研究者。