Year: 2021
Type: article
Abstract: Reactivation of human immunodeficiency virus 1 (HIV-1) from latently infected T cells is a critical barrier to successfully eradicate HIV-1 from patients. Latency models in Jurkat T-cells reveal that individual cells reactivate in an all-or-none fashion when exposed to latency reversal agents (LRAs). Remarkably, this heterogeneity arises within a clonal cell population of genetically identical cells containing a single copy of the provirus integrated at the same genomic site. 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 a period of colony expansion. If cellular responses are purely random, then the fraction of reactivating cells should have minimal colony-to-colony fluctuations given the large number of cells present after weeks of colony growth. In contrast, data shows considerable colony-to-colony fluctuations with the fraction of reactivating cells following a skewed distribution. Systematic measurements of fluctuations over time in combination with mathematical modeling uncovers the existence of a heritable memory that regulates HIV-1 reactivation, where single cells are in a 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 illustrate the utility of fluctuation-based assays to uncover hidden transient cellular states underlying phenotypic heterogeneity.
Source: iScience
Authors: Yiyang Lu, Harpal Singh, Abhyudai Singh, Roy D. Dar
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,000
Awards: G2035084605, Consequences and Control of Randomness in Timing of Intracellular, Stochastic hybrid systems approach to uncovering cell-size control mechanisms , G5992847402, G6609328350, G6972141254, G7206120639, G7813641274, CAREER: Viral control of cell migration in diverse host-cell types, Screening for modulators of Tat positive feedback for biasing HIV latency, G8211779461, G9000168604
OpenAlex ID: W3133520177