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ResearchIn-Press PreviewAIDS/HIV Open Access | 10.1172/jci.insight.179680

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

J. Natalie Howard,1 Thomas D. Zaikos,2 Callie Levinger,1 Esteban Rivera,1 Elyse K. McMahon,1 Carissa S. Holmberg,1 Joshua Terao,1 Marta Sanz,1 Dennis C. Copertino Jr.,1 Weisheng Wang,1 Natalia Soriano-Sarabia,1 R. Brad Jones,3 and Alberto Bosque1

1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

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1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

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1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

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1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

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1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

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1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

Find articles by Holmberg, C. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

Find articles by Terao, J. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

Find articles by Sanz, M. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

Find articles by Copertino Jr., D. in: JCI | PubMed | Google Scholar |

1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

Find articles by Wang, W. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

Find articles by Soriano-Sarabia, N. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

Find articles by Jones, R. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America

2Department of Pathology, Johns Hopkins Hospital, Baltimore, United States of America

3Department of Medicine, Weill Cornell College of Medicine, New York, United States of America

Find articles by Bosque, A. in: JCI | PubMed | Google Scholar |

Published August 8, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.179680.
Copyright © 2024, Howard et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 8, 2024 - Version history
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Abstract

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.

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