Suppression of Foxo1 activity and down-modulation of CD62L (L-selectin) in HIV-1 infected resting CD4 T cells.
Suppression of Foxo1 activity and down-modulation of CD62L (L-selectin) in HIV-1 infected resting CD4 T cells.
复制标题
DOI：
10.1371/journal.pone.0110719
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Levy DN
中科院分区：
文献类型：
--
作者：
Trinité B;Chan CN;Lee CS;Mahajan S;Luo Y;Muesing MA;Folkvord JM;Pham M;Connick E;Levy DN
HIV-1劫持和破坏它感染的细胞中的许多过程，以抑制抗病毒免疫并促进其复制。静息的CD 4 T细胞是HIV-1感染的重要早期靶点，其中HIV-1必须克服病毒复制的内在障碍。虽然静息的CD 4 T细胞在体外不易感染，但淋巴和粘膜组织内的局部环境因素如细胞因子促进病毒复制，同时维持静息状态。这些因子可用于体外研究HIV-1在静息CD 4 T细胞中的复制。在体内，静息幼稚T细胞和中枢记忆T细胞向淋巴组织中的迁移依赖于CD 62 L（L-选择素）的表达，CD 62 L是一种在T细胞活化后随后下调的受体。CD 62 L基因转录通过Foxo 1和KLF 2在静息T细胞中维持，Foxo 1和KLF 2是维持T细胞静止并调节其他细胞过程（包括存活、迁移和分化）的转录因子。在这里，我们报告说，HIV-1下调CD 62 L在生产性感染的幼稚和记忆静息CD 4 T细胞，同时抑制Foxo 1活性和KLF 2 mRNA的表达。部分T细胞活化进一步明显为CD 69表达的增加。在生产性感染的CD 4 T细胞中，其他几种Foxo 1和KLF 2调节的mRNA增加或减少，包括IL-7 r α、Myc、CCR 5、Fam 65 b、S1 P1（EDG 1）、CD 52、Cyclin D2和p21 CIP 1，表明这些细胞发生了深刻的重编程。Foxo 1抑制剂AS 1842856加速了病毒基因的重新表达和感染的后遗症，支持了HIV-1抑制Foxo 1活性可能是促进静息CD 4 T细胞复制的一种策略的观点。由于Foxo 1是一个研究性的癌症治疗靶点，Foxo 1干预措施的发展可能有助于寻求特异性抑制或激活体内HIV-1复制。
HIV-1 hijacks and disrupts many processes in the cells it infects in order to suppress antiviral immunity and to facilitate its replication. Resting CD4 T cells are important early targets of HIV-1 infection in which HIV-1 must overcome intrinsic barriers to viral replication. Although resting CD4 T cells are refractory to infection in vitro, local environmental factors within lymphoid and mucosal tissues such as cytokines facilitate viral replication while maintaining the resting state. These factors can be utilized in vitro to study HIV-1 replication in resting CD4 T cells. In vivo, the migration of resting naïve and central memory T cells into lymphoid tissues is dependent upon expression of CD62L (L-selectin), a receptor that is subsequently down-modulated following T cell activation. CD62L gene transcription is maintained in resting T cells by Foxo1 and KLF2, transcription factors that maintain T cell quiescence and which regulate additional cellular processes including survival, migration, and differentiation. Here we report that HIV-1 down-modulates CD62L in productively infected naïve and memory resting CD4 T cells while suppressing Foxo1 activity and the expression of KLF2 mRNA. Partial T cell activation was further evident as an increase in CD69 expression. Several other Foxo1- and KLF2-regulated mRNA were increased or decreased in productively infected CD4 T cells, including IL-7rα, Myc, CCR5, Fam65b, S1P1 (EDG1), CD52, Cyclin D2 and p21CIP1, indicating a profound reprogramming of these cells. The Foxo1 inhibitor AS1842856 accelerated de novo viral gene expression and the sequella of infection, supporting the notion that HIV-1 suppression of Foxo1 activity may be a strategy to promote replication in resting CD4 T cells. As Foxo1 is an investigative cancer therapy target, the development of Foxo1 interventions may assist the quest to specifically suppress or activate HIV-1 replication in vivo.
登录
查看更多内容
影响因子：
8.7
作者：
Estes JD
通讯作者：
Estes JD
Akt 抑制剂作为 HIV-1 感染巨噬细胞特异性抗病毒疗法。
影响因子：
3.3
作者：
Chugh, Pauline;Bradel-Tretheway, Birgit;Monteiro-Filho, Carlos Mr;Planelles, Vicente;Maggirwar, Sanjay B.;Dewhurst, Stephen;Kim, Baek
通讯作者：
Kim, Baek
影响因子：
56.9
作者：
Butcher, EC;Picker, LJ
通讯作者：
Picker, LJ
影响因子：
3.7
作者：
Chowdhury, IH;Wang, XF;Kim, JH
通讯作者：
Kim, JH
影响因子：
32.4
作者：
Eckstein, DA;Penn, ML;Goldsmith, MA
通讯作者：
Goldsmith, MA