Effect of Statins on HIV-1 Biology

描述（由申请人提供）：Craig Fletcher博士是一名兽医，目前正在接受实验动物医学的博士后研究项目，他将通过独特的比较医学临床培训和正式的博士培训来继续扩展他的科学技能。本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项目，最终将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，利用动物模型来研究HIV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白细胞免疫化学实验室进行，在发起人James E. K. Hildreth博士的指导下进行。候选人的培训计划包括在现代分子技术和研究方法方面的实验室和教学培训，并将其应用于艾滋病动物模型。

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.