期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 27, 页码 15763-15771出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1916290117
关键词
HIV; latency; reservoir; LRA; HSF1
资金
- Delaney AIDS Research Enterprise (DARE) [UM1 AI12661]
- Johns Hopkins Center for AIDS Research [P30AI094189]
- NIH [UM1 AI126603, UM1 AI126620, 43222, T32 GM007445]
- Howard Hughes Medical Institute
- Bill and Melinda Gates Foundation [OPP1115715]
- Bill and Melinda Gates Foundation [OPP1115715] Funding Source: Bill and Melinda Gates Foundation
HIV-1 latency is a major barrier to cure. Identification of small molecules that destabilize latency and allow immune clearance of infected cells could lead to treatment-free remission. In vitro models of HIV-1 latency involving cell lines or primary cells have been developed for characterization of HIV-1 latency and high-throughput screening for latency-reversing agents (LRAs). We have shown that the majority of LRAs identified to date are relatively ineffective in cells from infected individuals despite activity in model systems. We showhere that, for diverse LRAs, latency reversal observed inmodel systems involves a heat shock factor 1 (HSF1)-mediated stress pathway. Small-molecule inhibition of HSF1 attenuated HIV-1 latency reversal by histone deactylase inhibitors, protein kinase C agonists, and proteasome inhibitors without interfering with the known mechanism of action of these LRAs. However, latency reversal by second mitochondria-derived activator of caspase (SMAC) mimetics was not affected by inhibition of HSF1. In cells from infected individuals, inhibition of HSF1 attenuated latency reversal by phorbol ester+ionomycin but not by anti-CD3+anti-CD28. HSF1 promotes elongation of HIV-1 RNA by recruiting P-TEFb to the HIV-1 long terminal repeat (LTR), and we show that inhibition of HSF1 attenuates the formation of elongated HIV-1 transcripts. We demonstrate that in vitro models of latency have higher levels of the P-TEFb subunit cyclin T1 than primary cells, which may explain why many LRAs are functional in model systems but relatively ineffective in primary cells. Together, these studies provide insights into why particular LRA combinations are effective in reversing latency in cells from infected individuals.
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