Off-Target Effect of Activation of NF-κB by HIV Latency Reversal Agents on Transposable Elements Expression.
Off-Target Effect of Activation of NF-κB by HIV Latency Reversal Agents on Transposable Elements Expression.
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DOI：
10.3390/v14071571
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发表时间：
2022-07-20
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影响因子：
--
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许多药物已经被评估可以从细胞储存库中重新激活HIV-1，但这些潜伏期反转剂(LRA)的非靶点效应仍然没有明确的定义。转座元件(TES)在HIV-1感染过程中被重新激活，但关于潜在的非靶点药物对TE表达的影响的研究一直很有限。我们分析了规范和非规范的NF-κB信号诱导的TES的差异表达。我们评价了PKC激动剂(Bryostatin和ingenol B)对记忆性CD4+T细胞TES表达的影响。肌醇B诱导38个差异表达的TES(17个HERV(45%)和21个L1(55%))。有趣的是，与其他记忆T细胞亚群相比，Bryostatin对效应记忆CD4+T细胞TE表达的影响更大，有121个(107个上调，14个下调)TE差异表达(DE)。其中HERV占31%(n=37)，L1占69%(n=84)。AZD5582可诱发753例DE TES，其中HERV 406例(54%)，L1 347例(46%)。综上所述，我们的发现表明，规范和非规范的NF-κB信号激活导致逆转录元件表达作为一种非靶标效应。此外，我们的数据强调了在根除HIV-1战略的背景下探索LRA与逆转录元件表达之间的相互作用的重要性。
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.
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影响因子：
11.1
作者：
Doorbar, John;Egawa, Nagayasu;Griffin, Heather;Kranjec, Christian;Murakami, Isao
通讯作者：
Murakami, Isao
Bryostatin通过PKC和NF-ĸB依赖性机制激活人类星形胶质细胞中的HIV-1潜在表达。
影响因子：
4.6
作者：
Díaz L;Martínez-Bonet M;Sánchez J;Fernández-Pineda A;Jiménez JL;Muñoz E;Moreno S;Álvarez S;Muñoz-Fernández MÁ
通讯作者：
Muñoz-Fernández MÁ
影响因子：
15.9
作者：
Falcinelli, Shane D.;Peterson, Jackson J.;Turner, Anne-Marie W.;Irlbeck, David;Read, Jenna;Raines, Samuel L. M.;James, Katherine S.;Sutton, Cameron;Sanchez, Anthony;Emery, Ann;Sampey, Gavin;Ferris, Robert;Allard, Brigitte;Ghofrani, Simon;Kirchherr, Jennifer L.;Baker, Caroline;Kuruc, JoAnn D.;Gay, Cynthia L.;James, Lindsey I.;Wu, Guoxin;Zuck, Paul;Rioja, Inmaculada;Furze, Rebecca C.;Prinjha, Rab K.;Howell, Bonnie J.;Swanstrom, Ronald;Browne, Edward P.;Strahl, Brian D.;Dunham, Richard M.;Archin, Nancie M.;Margolis, David M.
通讯作者：
Margolis, David M.
影响因子：
5.9
作者：
Díaz-Carballo D;Saka S;Acikelli AH;Homp E;Erwes J;Demmig R;Klein J;Schröer K;Malak S;D'Souza F;Noa-Bolaño A;Menze S;Pano E;Andrioff S;Teipel M;Dammann P;Klein D;Nasreen A;Tannapfel A;Grandi N;Tramontano E;Ochsenfarth C;Strumberg D
通讯作者：
Strumberg D
影响因子：
4.3
作者：
Bendall, Matthew L.;de Mulder, Miguel;Nixon, Douglas F.
通讯作者：
Nixon, Douglas F.