PDF(Pubmed)
Abstract：
Human immunodeficiency virus-1 (HIV-1) infection can cause chronic activation, exhaustion, and anergy of the immune system. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an immune checkpoint molecule, which plays an important role in immune homeostasis and disease. CTLA-4 expression is elevated in HIV-1-infected patients and is associated with disease progression. However, the mechanism controlling expression of CTLA-4 in HIV-1 infection is poorly characterized. In this study, we used a SIV-infected Chinese rhesus macaque (ChRM) model to explore CTLA-4 expression in SIV infection. Results showed that SIV infection significantly increased CTLA-4 expression in all T cell subsets, especially central memory T cells. CTLA-4+CD4+ T cell frequency was significantly associated with disease progression markers. Activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway regulated CTLA-4 expression in CD4+T cells, as confirmed by stimulation with dibutyryl cyclic adenosine monophosphate, forskolin, and 3-isobutyl-1-methylxanthine, and inhibition with H-89 ex vivo. Simultaneously, cAMP concentration in PBMCs and PKA activity in both PBMCs and CD4+ T cells were increased in acute SIV-infected ChRMs, accompanied by an increase in adenylate cyclase 6 expression and a decrease in cAMP-phosphodiesterase 3A (PDE3A), PDE4B, and PDE5A expression in PBMCs. In addition, selective inhibition of PDE4B and PDE5A activity enhanced CTLA-4 expression in CD4+ T cells. These results suggest that SIV infection alters cAMP metabolism and increases cAMP-PKA signaling pathway activation, which up-regulates the expression of CTLA-4 in acute SIVmac239-infected ChRMs. Thus, regulation of the cAMP-PKA signaling pathway may be a potential strategy for the restoration of T cell function and therapy for AIDS.
摘要：
人类免疫缺陷病毒-1（HIV-1）感染可引起慢性激活，疲惫,和免疫系统的无能。细胞毒性T淋巴细胞相关抗原-4（CTLA-4）是一种免疫检查点分子，在免疫稳态和疾病中起着重要作用。CTLA-4表达在HIV-1感染患者中升高,并且与疾病进展相关。然而,在HIV-1感染中控制CTLA-4表达的机制缺乏表征。在这项研究中,我们使用SIV感染的中国恒河猴（ChRM）模型来探索SIV感染中CTLA-4的表达。结果显示，SIV感染显著增加CTLA-4在所有T细胞亚群中的表达，尤其是中枢记忆T细胞.CTLA-4+CD4+T细胞频率与疾病进展标志物显著相关。环磷酸腺苷（cAMP）-蛋白激酶A（PKA）信号通路的激活调节CD4+T细胞中CTLA-4的表达，如用二丁酰基环磷酸腺苷刺激所证实的，forskolin,和3-异丁基-1-甲基黄嘌呤，和用H-89离体抑制。同时,在急性SIV感染的ChRM中，PBMC中的cAMP浓度和PBMC和CD4T细胞中的PKA活性均增加，伴随着腺苷酸环化酶6表达的增加和cAMP-磷酸二酯酶3A（PDE3A）的减少，PDE4B,和PDE5A在PBMC中的表达。此外,选择性抑制PDE4B和PDE5A活性可增强CD4+T细胞中CTLA-4的表达。这些结果表明，SIV感染改变了cAMP代谢并增加了cAMP-PKA信号通路的激活，在急性SIVmac239感染的ChRM中上调CTLA-4的表达。因此，调节cAMP-PKA信号通路可能是恢复T细胞功能和治疗AIDS的潜在策略。
