报告人：Dr. Eric O. Freed，美国国家卫生研究院(NIH) 肿瘤研究所(NCI)首席研究员
地 点：北京大学综合科研楼137 会议室
Maturation Inhibitors (MI), a new class of HIV-1 antiretroviral drugs, act by blocking the maturation of virions into infectious particles. Bevirimat (BVM), the first-in-class HIV-1 maturation inhibitor, acts by blocking a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. BVM was shown to be safe and effective in reducing viral loads in HIV-1-infected patients. However, polymorphisms in the SP1 region of Gag reduced HIV-1 susceptibility to BVM in patients, effectively halting BVM’s clinical development. We carried out an extensive screening to identify BVM derivatives that demonstrate both increased potency against consensus strains of multiple HIV-1 clades and activity against primary isolates containing polymorphisms in SP1. Selection experiments were performed to identify mutations that confer resistance to the compounds; virological, structural, and molecular approaches were applied to elucidate the mechanism of resistance for each mutant. This study identifies a panel of BVM derivatives that display improvements relative to BVM in antiviral potency and breadth of activity. The characterization of resistant mutants provides insights into the structure of the maturation inhibitor binding site and the role of SP1 and the CA MHR in virus assembly and maturation.
Recent studies have also led to the surprising finding that mutations in the viral envelope (Env) glycoprotein confer broad replication advantages and resistance to antiretroviral drugs. These findings will be discussed.
Eric O. Freed博士是美国国家卫生研究院(NIH) 肿瘤研究所(NCI)的首席研究员, 致力于HIV与其它逆转录病毒的分子机制以及病毒相关疾病的治疗等方面的研究。现任美国HIV动态变化与复制研究项目部（HIV Dynamics and Replication Program）主任、美国NIH艾滋病发现与治疗方法研究组主席 (AIDS Discovery and Development of Therapeutics NIH Study Section)、美国NIH病毒学研究组主席(NIH Virology Interest Group)等。Dr. Freed于1985年在Pennsylvania State University 获得分子生物学学士学位, 1990年在University of Wisconsin-Madison获得细胞与分子生物学博士学位, 1992-1997年在NIH过敏与感染性疾病究所(NIAID) Malcolm Martin实验室从事研究，之后在NIH成立自己的实验室。现已在Nature、 Cell、Science等高影响因子杂志上发表文章180余篇。是国际著名的HIV分子病毒学专家。