Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure

作者：KM Rifat Faysal, James C. Walsh, Nadine Renner, Chantal L. Márquez, Vaibhav B. Shah, Andrew Tuckwell, Michelle P. Christie, Michael W. Parker, Stuart Grant Turville, Greg J. Towers, Leo C. James, David Anthony Jacques, Till Böcking · 发表于：eLife · 年份：2024 · DOI：10.7554/elife.83605 · 被引用次数：49 · 研究领域：HIV Research and Treatment、HIV/AIDS drug development and treatment、Parvovirus B19 Infection Studies

The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.