The HIV latency reversing agent HODHBt inhibits the phosphatases PTPN1 and PTPN2.

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.