非受体酪氨酸磷酸酶（NTP）在调节蛋白质磷酸化方面发挥着重要作用，并已被提议作为癌症和代谢疾病的有吸引力的治疗靶点。我们之前已经发现，3-Hydroxy-1,2,3-Benzotriazin-4(3H)-one (HODHBt) 在细胞因子刺激下增强 STAT 激活，从而增加潜在 HIV 的再激活以及 NK 和 CD8 T 细胞的效应功能。在这里，我们证明了 HODHBt 通过混合抑制机制与 NTP PTPN1 和 PTPN2 相互作用并抑制 NTPs PTPN1 和 PTPN2。我们还证实 PTPN1 和 PTPN2 特异性控制不同 STAT 的磷酸化。小分子 ABBV-CLS-484 (AC-484) 是 PTPN1 和 PTPN2 活性位点抑制剂，目前正在进行晚期实体瘤的临床试验。我们比较了 AC-484 和 HODHBt，发现对 STAT5 和免疫激活有相似的影响，尽管作用机制不同，导致对潜伏期逆转的影响不同。我们的研究提供了第一个具体证据，证明通过抑制 PTPN1 和 PTPN2 增强 STAT 磷酸化是对抗 HIV 的有效工具。

Nonreceptor tyrosine phosphatases (NTPs) play an important role regulating protein phosphorylation and have been proposed as attractive therapeutic targets for cancer and metabolic diseases. We have previously identified that 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhanced STAT activation upon cytokine stimulation leading to increased reactivation of latent HIV and effector functions of NK and CD8 T cells. Here, we demonstrated that HODHBt interacts with and inhibits the NTPs PTPN1 and PTPN2 through a mixed inhibition mechanism. We also confirmed that PTPN1 and PTPN2 specifically control the phosphorylation of different STATs. The small molecule ABBV-CLS-484 (AC-484) is an active site inhibitor of PTPN1 and PTPN2 currently in clinical trials for advanced solid tumors. We compared AC-484 and HODHBt and found similar effects on STAT5 and immune activation albeit with different mechanisms of action leading to varying effects on latency reversal. Our studies provide the first specific evidence that enhancing STAT phosphorylation via inhibition of PTPN1 and PTPN2 is an effective tool against HIV.