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

Abstract

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.

A Systems Biology Approach on the Regulatory Footprint of Human Endogenous Retroviruses (HERVs)

“…This result is in accordance with the bibliography and supports previous findings. Importantly HIV-1 infection is also associated with NF-κB signaling activation and transposable elements activation [ 124 ], which may suggest that HIV-1 and HERVs might be interconnected through a positive-feedback mechanism that involves inflammation induction and NF-κB activation.…”

HERVs: Expression Control Mechanisms and Interactions in Diseases and Human Immunodeficiency Virus Infection

“…HIV-1 Tat protein can recruit HATs to change the state of the chromatin and lead to the expression of HIV once it is integrated. However, this chromatin remodeling also leads to the expression of the HK2 through the pathway of NF-κB and nuclear factor of activated T-cell (NF-AT) transcription factors [88]. Tat through these pathways also leads to the activation of HK2 LTR promoters.…”