Hallmarks of Retroelement Expression in T-Cells Treated With HDAC Inhibitors

Abstract

A wide spectrum of drugs have been assessed as latency reversal agents (LRA) to reactivate HIV-1 from cellular reservoirs and aid in viral eradication strategies. Histone deacetylase inhibitors (HDACi) have been studied in vitro and in vivo as potential candidates for HIV-1 latency reversion. Suberoylanilide hydroxamic acid (SAHA) and romidepsin (RMD) are two HDACi able to reverse HIV latency, however studies of potential off-target effects on retroelement expression have been limited. Retroelements constitute a large portion of the human genome, and some are considered “fossil viruses” as they constitute remnants of ancient exogenous retroviruses infections. Retroelements are reactivated during certain disease conditions like cancer or during HIV-1 infection. In this study, we analyzed differential expression of retroelements using publicly available RNA-seq datasets (GSE102187 and GSE114883) obtained from uninfected CD4+, and HIV-1 latently infected CD4+ T-cells treated with HDACi (SAHA and RMD). We found a total of 712 and 1,380 differentially expressed retroelements in HIV-1 latently infected cells following a 24-h SAHA and RMD treatment, respectively. Furthermore, we found that 531 retroelement sequences (HERVs and L1) were differentially expressed under both HDACi treatments, while 1,030 HERV/L1 were exclusively regulated by each drug. Despite differences in specific HERV loci expression, the overall pattern at the HERV family level was similar for both treatments. We detected differential expression of full-length HERV families including HERV-K, HERV-W and HERV-H. Furthermore, we analyzed the link between differentially expressed retroelements and nearby immune genes. TRAF2 (TNF receptor) and GBP5 (inflammasome activator) were upregulated in HDACi treated samples and their expression was correlated with nearby HERV (MERV101_9q34.3) and L1 (L1FLnI_1p22.2k, L1FLnI_1p22.2j, L1FLnI_1p22.2i). Our findings suggest that HDACi have an off-target effect on the expression of retroelements and on the expression of immune associated genes in treated CD4+ T-cells. Furthermore, our data highlights the importance of exploring the interaction between HIV-1 and retroelement expression in LRA treated samples to understand their role and impact on “shock and kill” strategies and their potential use as reservoir biomarkers.

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

“…The HIV genome can be stabilized into cellular reservoirs through latent infection and can persist for decades in the human body. Thus, many drugs have been evaluated to reactivate and eliminate HIV-1 from reservoirs but their transcriptional reactivation is non-specific, and off-target effects have been reported [ 9 , 10 , 11 , 34 , 35 ]. In this study, we analyzed the off-target effects on the expression of retroelements in memory T cells treated with Bryostatin, Ingenol B and AZD5582, which are able to induce NF-κB signaling pathways.…”

“…Therapeutic strategies are focused on how to eliminate the HIV-1 reservoir, one approach is known as the “shock and kill strategy”, in which latency reversal agents (LRA) reactivate HIV-1 from cellular reservoirs (shock) for elimination by ART treatment (kill) [ 7 , 8 ]. However, LRAs are not specific for HIV-1 reactivation, and they can also impact on the expression of other genes such as transposable elements (TE) [ 9 , 10 , 11 ].…”

“…Differential HERV and L1 expression has been reported during LRA treatment [ 9 , 10 ]. However, the effect of newer LRAs such as bryostatin-1 and ingenol-3-hexanoate (Ingenol B) on TE expression has not been investigated.…”

Shock and kill within the CNS: A promising HIV eradication approach?

“…Therefore, most contemporary LRAs are designed to more specifically activate HIV, for instance by preferential methylation of HIV DNA as discussed in section 3.2. 167 Nevertheless, current LRAs are not exclusively reactivating HIV‐infected cells resulting in immune activation and toxicity in bystander cells, as discussed for CD4 + T cells 157,167–169 . It is suggestive that activation of noninfected cells in the CNS may lead to toxicity in these bystander cells as well.…”

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

“…Histone acetylation of ERVs loci should theoretically de-repress their transcription. However, conflicting data have been reported in this regard by using Histone Deacetylase (HDAC) inhibitors ( 39 , 40 ). DNA methylation and histone deacetylation may act as integrated mechanisms to ensure a concerted repression of latent retroviral elements.…”