Off-Target Effect of Activation of NF-κB by HIV Latency Reversal Agents on Transposable Elements Expression

Viruses. 2022 Jul 20;14(7):1571. doi: 10.3390/v14071571.


Many drugs have been evaluated to reactivate HIV-1 from cellular reservoirs, but the off-target effects of these latency reversal agents (LRA) remain poorly defined. Transposable elements (TEs) are reactivated during HIV-1 infection, but studies of potential off-target drug effects on TE expression have been limited. We analyzed the differential expression of TEs induced by canonical and non-canonical NF-κB signaling. We evaluated the effect of PKC agonists (Bryostatin and Ingenol B) on the expression of TEs in memory CD4+ T cells. Ingenol B induced 38 differentially expressed TEs (17 HERV (45%) and 21 L1 (55%)). Interestingly, TE expression in effector memory CD4+ T cells was more affected by Bryostatin compared to other memory T-cell subsets, with 121 (107 upregulated and 14 downregulated) differentially expressed (DE) TEs. Of these, 31% (n = 37) were HERVs, and 69% (n = 84) were LINE-1 (L1). AZD5582 induced 753 DE TEs (406 HERV (54%) and 347 L1 (46%)). Together, our findings show that canonical and non-canonical NF-κB signaling activation leads to retroelement expressions as an off-target effect. Furthermore, our data highlights the importance of exploring the interaction between LRAs and the expression of retroelements in the context of HIV-1 eradication strategies.

Keywords: CD4+ T cells; HERV; HIV-1; LINE-1; PKC activation; T-cell subsets; human endogenous retroviruses; latency reversal agents; transposable elements.

Publication types

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

MeSH terms

  • Bryostatins / pharmacology
  • CD4-Positive T-Lymphocytes / metabolism
  • DNA Transposable Elements*
  • Diterpenes / pharmacology
  • HIV Infections* / drug therapy
  • HIV Infections* / metabolism
  • HIV Seropositivity*
  • HIV-1
  • Humans
  • NF-kappa B* / metabolism
  • Virus Activation
  • Virus Latency*


  • Bryostatins
  • DNA Transposable Elements
  • Diterpenes
  • NF-kappa B
  • ingenol