Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo.
Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo.
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DOI：
10.1016/j.xcrm.2020.100037
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发表时间：
2020-06-23
期刊：
影响因子：
--
通讯作者：
Chanda SK
中科院分区：
文献类型：
--
作者：
Pache L;Marsden MD;Teriete P;Portillo AJ;Heimann D;Kim JT;Soliman MSA;Dimapasoc M;Carmona C;Celeridad M;Spivak AM;Planelles V;Cosford NDP;Zack JA;Chanda SK
“休克和杀死”策略的重点是通过用激活潜伏病毒的治疗剂治疗感染个体并随后消除感染细胞来清除潜伏的HIV-1储存库。我们以前曾报道过，通过一类称为Smac模拟物的小分子拮抗剂诱导非经典核因子κB（NF-κB）信号传导可以逆转HIV-1潜伏期。在这里，我们描述了Ciapavir（SBI-0953294）的开发，Ciapavir是一种专门针对HIV-1潜伏期逆转进行优化的分子，被发现作为潜伏期逆转剂比其他Smac模拟物在癌症临床开发中更有效。重要的是，该分子在骨髓、肝脏、胸腺（BLT）人源化小鼠模型中体内诱导HIV-1储库的活化，而不介导系统性T细胞活化。这项研究为Ciapavir的体内疗效和安全性提供了概念证明，并表明Smac模拟物可以构成消除潜伏HIV-1储库的安全有效治疗策略的关键组分。Ciapavir是一种有效的Smac模拟物，专门针对HIV-1潜伏期逆转进行了优化Smac模拟物与溴结构域抑制剂协同作用逆转HIV-1潜伏期Ciapavir耐受性良好，不会诱导广泛的免疫激活Ciapavir的全身给药介导小鼠模型中的潜伏期逆转Pache et al.报道了Ciapavir的开发，Ciapavir是一种针对HIV-1潜伏期逆转而优化的有效小分子Smac模拟物。Ciapavir在小鼠中显示出良好的药代动力学和药效学特性，并在不存在全身免疫激活的人源化小鼠模型中诱导体内潜伏的HIV-1储库的激活。
“Shock and kill” strategies focus on purging the latent HIV-1 reservoir by treating infected individuals with therapeutics that activate the latent virus and subsequently eliminating infected cells. We have previously reported that induction of non-canonical nuclear factor κB (NF-κB) signaling through a class of small-molecule antagonists known as Smac mimetics can reverse HIV-1 latency. Here, we describe the development of Ciapavir (SBI-0953294), a molecule specifically optimized for HIV-1 latency reversal that was found to be more efficacious as a latency-reversing agent than other Smac mimetics under clinical development for cancer. Critically, this molecule induced activation of HIV-1 reservoirs in vivo in a bone marrow, liver, thymus (BLT) humanized mouse model without mediating systemic T cell activation. This study provides proof of concept for the in vivo efficacy and safety of Ciapavir and indicates that Smac mimetics can constitute a critical component of a safe and efficacious treatment strategy to eliminate the latent HIV-1 reservoir. Ciapavir is a potent Smac mimetic specifically optimized for HIV-1 latency reversal Smac mimetics synergize with bromodomain inhibitors to reverse HIV-1 latency Ciapavir is well tolerated and does not induce broad immune activation Systemic administration of Ciapavir mediates latency reversal in a mouse model Pache et al. report the development of Ciapavir, a potent small-molecule Smac mimetic optimized for HIV-1 latency reversal. Ciapavir shows favorable pharmacokinetic and pharmacodynamic properties in mice and induces activation of the latent HIV-1 reservoir in vivo in a humanized mouse model in the absence of systemic immune activation.
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影响因子：
7.3
作者：
Cai Q;Sun H;Peng Y;Lu J;Nikolovska-Coleska Z;McEachern D;Liu L;Qiu S;Yang CY;Miller R;Yi H;Zhang T;Sun D;Kang S;Guo M;Leopold L;Yang D;Wang S
通讯作者：
Wang S
DOI：
10.3390/v5061571
发表时间：
2013-06-21
期刊：
Viruses
影响因子：
--
作者：
Boehm D;Conrad RJ;Ott M
通讯作者：
Ott M
影响因子：
64.8
作者：
Borducchi, Erica N.;Cabral, Crystal;Stephenson, Kathryn E.;Liu, Jinyan;Abbink, Peter;Ng'ang'a, David;Nkolola, Joseph P.;Brinkman, Amanda L.;Peter, Lauren;Lee, Benjamin C.;Jimenez, Jessica;Jetton, David;Mondesir, Jade;Mojta, Shanell;Chandrashekar, Abishek;Molloy, Katherine;Alter, Galit;Gerold, Jeffrey M.;Hill, Alison L.;Lewis, Mark G.;Pau, Maria G.;Schuitemaker, Hanneke;Hesselgesser, Joseph;Geleziunas, Romas;Kim, Jerome H.;Robb, Merlin L.;Michael, Nelson L.;Barouch, Dan H.
通讯作者：
Barouch, Dan H.
影响因子：
2.7
作者：
DiPersio, John F.;Erba, Harry P.;Zanna, Claudio
通讯作者：
Zanna, Claudio
影响因子：
6.4
作者：
Archin, Nancy M.;Bateson, Rosalie;Margolis, David M.
通讯作者：
Margolis, David M.