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

描述（由申请人提供）：全球艾滋病毒/艾滋病流行继续扩大，主要是由病毒的性传播和静脉注射吸毒者之间共用受污染的针头驱动的。全球基金和PEPFAR这两个国际项目为发展中国家提供了最大份额的抗病毒药物，但却无法跟上发展中国家的步伐。 疫每10名接受抗病毒治疗的受试者中，就有16名新感染。随着感染人数的增加和用于终身治疗的资金越来越有限，艾滋病毒/艾滋病护理方面将不可避免地出现严重缺口。我们可以做些什么来缩小这一差距？引人注目的是，慢病毒（如HIV-1）带来的致病性挑战已经在40多种与慢病毒共同进化的猴子中得到了成功的解决。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，因为它们没有产生慢性炎症和免疫激活反应，比如在艾滋病毒感染的人类中发现的那些反应。我们最近发现，在HIV感染的淋巴组织中死亡的绝大多数CD 4 T细胞是一种强烈的炎症形式的程序性细胞死亡的受害者，称为pyroptosis，它涉及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/炎性小体/细胞凋亡途径的小分子抑制剂是否可以阻断艾滋病的临床进展。Caspase-1抑制剂已经进入临床试验。如果成功的话，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。" P

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