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: 9503875
• 负责人: Warner C. Greene
• 金额: $ 16.62万
• 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/9503875
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Animals; Antiviral Agents; Antiviral Therapy; Apoptosis; Biological; CASP1 gene; CD4 Positive T Lymphocytes; Caring; Chronic; Clinical; Clinical Trials; Disease; Disease Progression; Dreams; Drug usage; Epidemic; Funding; Generations; HIV; HIV Infections; HIV-1; Human; Immune response; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Injectable; International; Lymphoid Tissue; Monkeys; Needles; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Risk; Sexual Transmission; Subfamily lentivirinae; Therapeutic; Virus; base; cost effective; immune activation; inhibitor/antagonist; interleukin-1beta-converting enzyme inhibitor; intravenous drug user; novel; prevent; programs; response; small molecule inhibitor; viral transmission

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

描述（由申请人提供）：全球艾滋病毒/艾滋病流行继续扩大，主要是由于病毒的性传播和静脉吸毒者共用受污染的针头所致。全球基金和总统防治艾滋病紧急救援计划这两个为发展中国家提供大部分抗病毒药物的国际计划，却无法跟上 流行。每 10 名接受抗病毒治疗的受试者中，就有 16 名新感染者。随着感染人数的增加和终身治疗的资金变得更加有限，艾滋病毒/艾滋病护理将不可避免地出现严重缺口。可以采取什么措施来缩小这一差距？引人注目的是，慢病毒（例如 HIV-1）带来的致病性挑战已在 40 多种与慢病毒共同进化的猴子身上成功得到解决。令人惊讶的是，解决方案不是抑制病毒，而是以预防疾病的方式改变宿主对病毒的反应。这些动物基本上“忽略”了它们的慢病毒，因为它们未能产生慢性炎症和免疫激活反应，例如在感染艾滋病毒的人类中发现的反应。我们最近发现，在 HIV 感染的淋巴组织中死亡的绝大多数 CD4 T 细胞是一种称为焦亡的强烈炎症性程序性细胞死亡的受害者，这种死亡涉及 caspase-1 激活和炎性小体组装。值得注意的是，该途径似乎在致病性而非非致病性慢病毒感染中被选择性激活。我们现在建议确定 caspase 1/炎症小体/细胞焦亡途径的小分子抑制剂是否可以阻止 AIDS 的临床进展。 Caspase-1 抑制剂已进入临床试验。如果成功，这种以宿主为中心的策略可以作为一种新颖且具有成本效益的手段来预防疾病进展，从而有可能改变数百万无法获得抗病毒治疗的艾滋病毒感染者的护理。这种方法可以帮助实现“无艾滋病一代”的梦想。 磷