HIV without AIDS: A Radically Different Approach to Help the Developing World

没有艾滋病的艾滋病毒：帮助发展中国家的完全不同的方法

• 批准号: 8606334
• 负责人: Warner C. Greene
• 金额: $ 95.5万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606334
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Animals; Antiviral Agents; Antiviral Therapy; Apoptosis; CD4 Positive T Lymphocytes; Caring; Caspase-1; Chronic; Clinical; Clinical Trials; Disease; Disease Progression; Dreams; Epidemic; Funding; Generations; HIV; HIV-1; Human; Immune response; Individual; Infection; Inflammatory; International; Lymphoid Tissue; Monkeys; Needles; Pathway interactions; Sexual Transmission; Solutions; Subfamily lentivirinae; Virus; cost effective; immune activation; interleukin-1beta-converting enzyme inhibitor; intravenous drug user; meetings; novel; prevent; programs; response; small molecule

DESCRIPTION (provided by applicant): The global HIV/AIDS epidemic continues to expand, driven chiefly by sexual transmission of the virus and sharing of contaminated needles among intravenous drug users. The Global Fund and PEPFAR, the two international programs providing the lion's share of antiviral drugs in the developing world, are unable to keep pace with the epidemic. For every 10 subjects placed on antiviral therapy, 16 individuals are newly infected. As the number of infections increases and funds for lifelong treatment become more limited, a serious gap in HIV/AIDS care will inevitably emerge. What can be done to close this gap? Strikingly, the pathogenic challenge posed by lentiviruses, such as HIV-1, has been successfully met in 40+ species of monkeys who have coevolved with their lentiviruses. Surprisingly, the solution is not to suppress the virus, but rather to modify the host response to the virus in a manner that prevents disease. These animals essentially "ignore" their lentivirus, by failing to mount chronic inflammatory and immune activation responses, such as those found in HIV- infected humans. We recently found that the vast majority of CD4 T cells dying in HIV-infected lymphoid tissues are victims of an intensely inflammatory form of programmed cell death termed pyroptosis, which involves caspase-1 activation and inflammasome assembly. Remarkably, this pathway appears to be selectively activated in pathogenic but not non-pathogenic lentiviral infections. We now propose to determine if small-molecule inhibitors of the caspase 1/inflammasome/pyroptosis pathway can block clinical progression to AIDS. Caspase-1 inhibitors are already in clinical trials. If successful, this host-focused strategy could be use as a novel and cost-effective means to prevent disease progression, potentially transforming the care of millions of HIV-infected subjects who are unable to access antiviral therapy. This approach could help realize the dream of an "AIDS-free generation." P

说明（由申请人提供）：全球艾滋病毒/艾滋病流行病继续扩大，主要原因是病毒的性传播和静脉注射吸毒者共用受污染的针头。全球基金和PEPFAR这两个为发展中国家提供最大份额抗病毒药物的国际项目无法跟上