Enhanced antitumoral activity of TLR7 agonists via activation of human endogenous retroviruses by HDAC inhibitors

Díaz-Carballo, David; Saka, Sahitya; Acikelli, Ali Haydar; Homp, Ekaterina; Erwes, Julia; Demmig, Rebecca; Klein, Jacqueline; Schröer, Katrin; Malak, Sascha; D’Souza, Flevy; Noa-Bolaño, Adrien; Menze, Saskia; Pano, Emilio; Andrioff, Swetlana; Teipel, Marc; Dammann, Philip; Klein, Diana; Nasreen, Amber; Tannapfel, Andrea; Grandi, Nicole; Tramontano, Enzo; Ochsenfarth, Crista; Strumberg, Dirk

doi:10.1038/s42003-021-01800-3

Cited by 20 publications

(16 citation statements)

References 61 publications

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“…Different drugs have been reported to reverse HIV-1 latency such as HDACi, but they may also have off-target effects (43,45,50,51), including effects on retroelement expression (42,43), which can potentially lead to cellular dysfunction (5,10,52,53). Therefore, in this study we analyzed HERV and L1 differential expression at the single locus resolution level using Telescope bioinformatic pipeline in RNA-seq datasets from uninfected and HIV-1 latently infected CD4 + T-cells, treated with SAHA and RMD, two widely used HDACi.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

“…An important off-target effect of the shock and kill strategy is to induce expression of endogenous genes, including HERVs (42,43). Uninfected primary CD4 + T-cells treated with SAHA show upregulation of HERV-9 and LTR12 as well as downregulation of ERVL (43).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…A number of other studies, however, have reported synergy between TLR7/8 agonists and checkpoint inhibitors in various other murine tumor models [ 336 - 339 ]. Other attempts to augment the efficacy of synthetic TLR7/8 agonists have included combinations with antibodies such as anti-EGFR and anti-HER2/neu, cytokines such as IL-2, and photothermal therapies [ 340 - 345 ].…”

Section: Bioconjugation and Other Delivery Strategiesmentioning

confidence: 99%

Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants

Bhagchandani

Johnson

Irvine

2021

Advanced Drug Delivery Reviews

112

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“…Further, combination of TLR2/7 agonists with bnAbs [519,520] may be a valid strategy for clearance after reactivation and maintaining immune control, similar to the GS-9620 + bnAb PGT121 [519] or IL-15 superagonist (N-803) + bnAbs 10-1074 and 3BNC117 [521] studies. Interestingly, a cancer study showed that HDACis increase production of human endogenous retroviral elements in cancer cells and that concomitant treatment of TLR7/8 agonists allows for the cells to induce intrinsic apoptosis when they otherwise would not have enough stimuli to do so, while also at doses that are individually subcytotoxic [746]. This therapy can readily be applied to HIV research, but will first require ex vivo testing to ensure cell viability of uninfected cells is maintained and bystander death is not prolific.…”

Section: Crosstalk Between Macrophages and Exhausted T Cellsmentioning

confidence: 99%

So Pathogenic or So What?—A Brief Overview of SIV Pathogenesis with an Emphasis on Cure Research

Kleinman

Pandrea

Apetrei

2022

Viruses

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HIV infection requires lifelong antiretroviral therapy (ART) to control disease progression. Although ART has greatly extended the life expectancy of persons living with HIV (PWH), PWH nonetheless suffer from an increase in AIDS-related and non-AIDS related comorbidities resulting from HIV pathogenesis. Thus, an HIV cure is imperative to improve the quality of life of PWH. In this review, we discuss the origins of various SIV strains utilized in cure and comorbidity research as well as their respective animal species used. We briefly detail the life cycle of HIV and describe the pathogenesis of HIV/SIV and the integral role of chronic immune activation and inflammation on disease progression and comorbidities, with comparisons between pathogenic infections and nonpathogenic infections that occur in natural hosts of SIVs. We further discuss the various HIV cure strategies being explored with an emphasis on immunological therapies and “shock and kill”.

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Enhanced antitumoral activity of TLR7 agonists via activation of human endogenous retroviruses by HDAC inhibitors

Cited by 20 publications

References 61 publications

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

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

Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants

So Pathogenic or So What?—A Brief Overview of SIV Pathogenesis with an Emphasis on Cure Research

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