Long non-coding RNAs and latent HIV - A search for novel targets for latency reversal

PLoS One. 2019 Nov 11;14(11):e0224879. doi: 10.1371/journal.pone.0224879. eCollection 2019.

Abstract

The latent cellular reservoir of HIV is recognized as the major barrier to cure from HIV infection. Long non-coding RNAs (lncRNAs) are more tissue and cell type-specific than protein coding genes, and may represent targets of choice for HIV latency reversal. Using two in vitro primary T-cell models, we identified lncRNAs dysregulated in latency. PVT1 and RP11-347C18.3 were up-regulated in common between the two models, and RP11-539L10.2 was down-regulated. The major component of the latent HIV reservoir, memory CD4+ T-cells, had higher expression of these lncRNAs, compared to naïve T-cells. Guilt-by-association analysis demonstrated that lncRNAs dysregulated in latency were associated with several cellular pathways implicated in HIV latency establishment and maintenance: proteasome, spliceosome, p53 signaling, and mammalian target of rapamycin (MTOR). PVT1, RP11-347C18.3, and RP11-539L10.2 were down-regulated by latency reversing agents, suberoylanilide hydroxamic acid and Romidepsin, suggesting that modulation of lncRNAs is a possible secondary mechanism of action of these compounds. These results will facilitate prioritization of lncRNAs for evaluation as targets for HIV latency reversal. Importantly, our study provides insights into regulatory function of lncRNA during latent HIV infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Depsipeptides / pharmacology
  • Down-Regulation / drug effects
  • HIV-1 / drug effects
  • HIV-1 / genetics*
  • Humans
  • Immunologic Memory
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • T-Lymphocytes / immunology
  • Virus Latency / drug effects
  • Virus Latency / genetics*
  • Vorinostat / pharmacology

Substances

  • Depsipeptides
  • RNA, Long Noncoding
  • RNA, Messenger
  • Vorinostat
  • romidepsin