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首页> 外文期刊>Biochemical Pharmacology >Cytotoxic cell populations developed during treatment with tyrosine kinase inhibitors protect autologous CD4+T cells from HIV-1 infection
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Cytotoxic cell populations developed during treatment with tyrosine kinase inhibitors protect autologous CD4+T cells from HIV-1 infection

机译：用酪氨酸激酶抑制剂治疗期间开发的细胞毒性细胞群免受HIV-1感染保护自体CD4 + T细胞

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Tyrosine kinase inhibitors (TKIs) are successfully used in clinic to treat chronic myeloid leukemia (CML). Our group previously described that CD4+ T cells from patients with CML on treatment with TKIs such as dasatinib were resistant to HIV-1 infection ex vivo. The main mechanism for this antiviral activity was primarily based on the inhibition of SAMHD1 phosphorylation, which preserves the activity against HIV-1 of this innate immune factor. Approximately 50% CML patients who achieved a deep molecular response (DMR) may safely withdraw TKI treatment without molecular recurrence. Therefore, it has been speculated that TKIs may induce a potent antileukemic response that is maintained in most patients even one year after treatment interruption (TI). Subsequent to in vitro T-cell activation, we observed that SAMHD1 was phosphorylated in CD4+ T cells from CML patients who withdrew TKI treatment more than one year earlier, which indicated that these cells were now susceptible to HIV-1 infection. Importantly, these patients were seronegative for HIV-1 and seropositive for cytomegalovirus (CMV), but without CMV viremia. Although activated CD4+ T cells from CML patients on TI were apparently permissive to HIV-1 infection ex vivo, the frequency of proviral integration was reduced more than 12-fold on average when these cells were infected ex vivo in comparison with cells isolated from untreated, healthy donors. This reduced susceptibility to infection could be related to an enhanced NK-dependent cytotoxic activity, which was increased 8-fold on average when CD4+ T cells were infected ex vivo with HIV-1 in the presence of autologous NK cells. Enhanced cytotoxic activity was also observed in CD8 + T cells from these patients, which showed 8-fold increased expression of TCR gamma delta and more than 18-fold increased production of IFN gamma upon activation with CMV peptides. In conclusion, treatment with TKIs induced a potent antileukemic response that may also have antiviral effects against HIV-1 and CMV, suggesting that transient use of TKIs in HIV-infected patients could develop a sustained antiviral response that would potentially interfere with HIV-1 reservoir dynamics.
机译：酪氨酸激酶抑制剂（TKI）以临床成功用于治疗慢性髓性白血病（CML）。我们的小组以前描述了来自CML患者的CD4 + T细胞用TKI处理如Dasatinib的CML治疗，耐受HIV-1感染exVivo。该抗病毒活性的主要机制主要是基于Samhd1磷酸化的抑制，这保留了对该天生免疫因子的HIV-1的活性。实现了深度分子响应（DMR）的约50％CML患者可以安全地撤回TKI治疗而不进行分子复发。因此，已经推测，TKIS可以诱导甚至在治疗中断后一年的大多数患者维持的有效的抗血糖反应。在体外T细胞活化之后，我们观察到Samhd1在来自CML患者的CD4 + T细胞中磷酸化，其中患者以上一年多的TKI治疗，这表明这些细胞现在易受HIV-1感染的影响。重要的是，这些患者对HIV-1和塞细胞病毒（CMV）的血清阳性均为疫苗，但没有CMV病毒血症。虽然来自CML患者的TI患者的活化CD4 + T细胞显然允许HIV-1感染，但随着从未治疗的细胞感染离体，普通型集成的频率平均减少了12倍以上的12倍，健康的捐助者。这种对感染的易感性可能与增强的NK依赖性细胞毒性活性有关，当在自体NK细胞存在下用HIV-1感染CD4 + T细胞时，平均增加8倍。在来自这些患者的CD8 + T细胞中也观察到增强的细胞毒性活性，其显示出8倍的TCRγδ的表达，并且在用CMV肽激活时，IFNγ的产生增加的增加的IFNγ的产生。总之，随着TKI的治疗诱导有效的抗血糖反应，所述抗病毒反应也可能对HIV-1和CMV进行抗病毒影响，这表明TKIS在艾滋病毒感染患者中的瞬时使用可能会产生持续的抗病毒反应，可能会干扰HIV-1水库可能会干扰HIV-1水库动力学。

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