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标题：A transient heritable memory regulates HIV reactivation from latency
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作者：Yiyang Lu ; Harpal Singh ; Abhyudai Singh 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：4
页码：1-24
DOI：10.1016/j.isci.2021.102291
语种：English
出版社：Elsevier
摘要：SummaryReactivation of human immunodeficiency virus 1 (HIV-1) from latently infected T cells is a critical barrier to cure patients. It remains unknown whether reactivation of individual latent cells occurs stochastically in response to latency reversal agents (LRAs) or is a deterministic outcome of an underlying cell state. To characterize these single-cell responses, we leverage the classical Luria-Delbrück fluctuation test where single cells are isolated from a clonal population and exposed to LRAs after colony expansion. Data show considerable colony-to-colony fluctuations with the fraction of reactivating cells following a skewed distribution. Modeling systematic measurements of fluctuations over time uncovers a transient heritable memory that regulates HIV-1 reactivation, where single cells are in an LRA-responsive state for a few weeks before switching back to an irresponsive state. These results have enormous implications for designing therapies to purge the latent reservoir and further utilize fluctuation-based assays to uncover hidden transient cellular states underlying phenotypic heterogeneity.Graphical abstractDisplay OmittedHighlights•Jurkat HIV latency model (JLat) shows inheritable responsiveness to TNF-α stimulation•JLat cells may switch between responsive state and irresponsive state spontaneously•Mathematical modeling indicates a memory timescale on the order of monthsComputational Molecular Modeling; Virology