Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo.
Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo.
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DOI：
10.1172/jci.insight.162290
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发表时间：
2022-11-08
期刊：
影响因子：
8
通讯作者：
Martinelli, Elena
中科院分区：
文献类型：
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作者：
Samer, Sadia;Thomas, Yanique;Arainga, Mariluz;Carter, Crystal;Shirreff, Lisa M.;Arif, Muhammad S.;Avita, Juan M.;Frank, Ines;McRaven, Michael D.;Thuruthiyil, Christopher T.;Heybeli, Veli B.;Anderson, Meegan R.;Owen, Benjamin;Gaisin, Arsen;Bose, Deepanwita;Simons, Lacy M.;Hultquist, Judd F.;Arthos, James;Cicala, Claudia;Sereti, Irini;Santangelo, Philip J.;Lorenzo-Redondo, Ramon;Hope, Thomas J.;Villinger, Francois J.;Martinelli, Elena
TGF-β通过抑制细胞活化和增殖在维持免疫细胞处于静息状态中起关键作用。静止的HIV-1靶细胞是长期抗逆转录病毒治疗（ART）后的主要细胞库。我们假设从TGF-β驱动的信号中释放细胞将促进潜伏期逆转。为了验证我们的假设，我们比较了有和没有TGF-β和TGF-β 1型受体抑制剂galunisertib的HIV-1潜伏期模型。我们使用64 Cu-DOTA-F（ab′）2 p7 D3探针，沿着血浆和组织病毒载量（VL），通过PET/CT监测SIV-env表达，检测了galunisertib在SIV感染、ART治疗的猕猴中的作用。在U1和ACH-2模型中，外源性TGF-β可降低HIV-1再活化。Galunisertib增加了HIV-1感染、ART治疗、病毒血症供体的离体和PBMC中HIV-1潜伏期逆转。在体内，口服galunisertib促进了5/7只长期ART治疗的病毒血症SIV感染猕猴的肠道和淋巴结PET/CT图像中总标准化摄取值的增加。这种增加与肠道中SIV RNA的增加相关。7只动物中的2只也显示血浆VL增加。galunisertib治疗后检测到更高的抗SIV T细胞应答和抗体滴度。总之，我们的数据表明阻断TGF-β信号传导同时增加逆转录病毒再激活事件并增强抗SIV免疫应答。
TGF-β plays a critical role in maintaining immune cells in a resting state by inhibiting cell activation and proliferation. Resting HIV-1 target cells represent the main cellular reservoir after long-term antiretroviral therapy (ART). We hypothesized that releasing cells from TGF-β–driven signaling would promote latency reversal. To test our hypothesis, we compared HIV-1 latency models with and without TGF-β and a TGF-β type 1 receptor inhibitor, galunisertib. We tested the effect of galunisertib in SIV-infected, ART-treated macaques by monitoring SIV-env expression via PET/CT using the 64Cu-DOTA-F(ab′)2 p7D3 probe, along with plasma and tissue viral loads (VLs). Exogenous TGF-β reduced HIV-1 reactivation in U1 and ACH-2 models. Galunisertib increased HIV-1 latency reversal ex vivo and in PBMCs from HIV-1–infected, ART-treated, aviremic donors. In vivo, oral galunisertib promoted increased total standardized uptake values in PET/CT images in gut and lymph nodes of 5 out of 7 aviremic, long-term ART-treated, SIV-infected macaques. This increase correlated with an increase in SIV RNA in the gut. Two of the 7 animals also exhibited increases in plasma VLs. Higher anti-SIV T cell responses and antibody titers were detected after galunisertib treatment. In summary, our data suggest that blocking TGF-β signaling simultaneously increases retroviral reactivation events and enhances anti-SIV immune responses.
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DOI：
10.4049/jimmunol.1402623
发表时间：
2015-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Guerra-Pérez N;Frank I;Veglia F;Aravantinou M;Goode D;Blanchard JL;Gettie A;Robbiani M;Martinelli E
通讯作者：
Martinelli E
影响因子：
17.1
作者：
Frank I;Cigoli M;Arif MS;Fahlberg MD;Maldonado S;Calenda G;Pegu A;Yang ES;Rawi R;Chuang GY;Geng H;Liu C;Zhou T;Kwong PD;Arthos J;Cicala C;Grasperge BF;Blanchard JL;Gettie A;Fennessey CM;Keele BF;Vaccari M;Hope TJ;Fauci AS;Mascola JR;Martinelli E
通讯作者：
Martinelli E
影响因子：
56.9
作者：
FOLKS, TM;JUSTEMENT, J;FAUCI, AS
通讯作者：
FAUCI, AS
DOI：
10.1073/pnas.93.13.6377
发表时间：
1996-06-25
影响因子：
11.1
作者：
Emiliani, S;VanLint, C;Verdin, E
通讯作者：
Verdin, E
影响因子：
6.4
作者：
Dobrowolski, Curtis;Valadkhan, Saba;Karn, Jonathan
通讯作者：
Karn, Jonathan