Reactivation of latent HIV-1 in central memory CD4⁺ T cells through TLR-1/2 stimulation.
Reactivation of latent HIV-1 in central memory CD4⁺ T cells through TLR-1/2 stimulation.
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DOI：
10.1186/1742-4690-10-119
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发表时间：
2013-10-24
期刊：
影响因子：
3.3
通讯作者：
Bosque A
中科院分区：
文献类型：
--
作者：
Novis CL;Archin NM;Buzon MJ;Verdin E;Round JL;Lichterfeld M;Margolis DM;Planelles V;Bosque A
toll样受体（TLRs）对先天免疫系统细胞识别病原体相关分子模式至关重要。tlr在CD4+ T细胞中存在并起作用。记忆CD4+ T细胞，主要是中央记忆细胞（TCM），构成了潜伏HIV-1的主要储存库。然而，TLR配体如何影响中枢记忆CD4+ T细胞内潜伏HIV的静止尚未得到研究。我们评估了广泛的TLR激动剂重新激活潜伏HIV-1的能力。TLR-1/2激动剂Pam3CSK4在基于培养的中医潜伏期模型和病毒血症患者分离的静息CD4+ T细胞中导致静止HIV病毒再激活。此外，我们还研究了Pam3CSK4参与HIV-1再激活的相关信号通路。我们发现转录因子NFκB、NFAT和AP-1协同诱导TLR-1/2刺激下游的病毒再激活。此外，tlr介导的病毒再激活并不需要细胞周期蛋白T1水平的升高，但诱导病毒表达需要激活pTEFb。最后，与抗原刺激相比，Pam3CSK4在没有T细胞激活或增殖的情况下重新激活潜伏的HIV-1。我们的研究结果表明，应该探索通过Pam3CSK4或其他试剂通过TLR-1/2途径进行信号传导，作为单独或与其他抗延迟药物联合的抗延迟策略。
Toll-like receptors (TLRs) are crucial for recognition of pathogen-associated molecular patterns by cells of the innate immune system. TLRs are present and functional in CD4+ T cells. Memory CD4+ T cells, predominantly central memory cells (TCM), constitute the main reservoir of latent HIV-1. However, how TLR ligands affect the quiescence of latent HIV within central memory CD4+ T cells has not been studied. We evaluated the ability of a broad panel of TLR agonists to reactivate latent HIV-1. The TLR-1/2 agonist Pam3CSK4 leads to viral reactivation of quiescent HIV in a model of latency based on cultured TCM and in resting CD4+ T cells isolated from aviremic patients. In addition, we investigated the signaling pathway associated with Pam3CSK4 involved in HIV-1 reactivation. We show that the transcription factors NFκB, NFAT and AP-1 cooperate to induce viral reactivation downstream of TLR-1/2 stimulation. Furthermore, increasing levels of cyclin T1 is not required for TLR-mediated viral reactivation, but induction of viral expression requires activated pTEFb. Finally, Pam3CSK4 reactivates latent HIV-1 in the absence of T cell activation or proliferation, in contrast to antigen stimulation. Our findings suggest that the signaling through TLR-1/2 pathway via Pam3CSK4 or other reagents should be explored as an anti-latency strategy either alone or in combination with other anti-latency drugs.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
DOI：
10.1073/pnas.94.24.13193
发表时间：
1997-11-25
影响因子：
11.1
作者：
Chun, TW;Stuyver, L;Fauci, AS
通讯作者：
Fauci, AS
影响因子：
20.3
作者：
Bosque, Alberto;Planelles, Vicente
通讯作者：
Planelles, Vicente
影响因子：
3.8
作者：
Bernier, R;Barbeau, B;Tremblay, MJ
通讯作者：
Tremblay, MJ
影响因子：
4.8
作者：
Bosque, Alberto;Planelles, Vicente
通讯作者：
Planelles, Vicente