Novel Treatment for HIV Disease

University of Pittsburgh and Fox Chase Therapeutics Discovery, Inc. researchers have developed proteolysis targeting chimeras (PROTACs) for the targeted degradation of the HIV-1 Nef virulence factor. Nef-binding compounds, based on an existing hydroxypyrazole core, were coupled to ligands for ubiquitin E3 ligases via flexible linkers. The resulting bivalent PROTACs induce ternary complexes between Nef and the Cereblon E3 ubiquitin ligase and trigger Nef degradation in T cells. Nef-directed PROTACs efficiently rescue Nef-mediated MHC-I and CD4 downregulation in T cells and suppress HIV-1 replication in PBMCs. Successful development of this treatment approach may have profound impacts on people living with HIV, ultimately leading to a functional cure (long-term control of HIV replication without treatment). 

Description

Globally, about 40 million people are living with HIV, which can lead to AIDS, opportunistic infections and cancers. While HIV can be managed with lifelong administration of antiretroviral medications, no cure exists. A large body of research has identified the HIV Nef protein as a key to chronic HIV-1 infection, due to its ability to downregulate cell surface MHC-I and other receptors essential to immune system recognition of HIV-positive cells. Targeted degradation of Nef with Nef-directed PROTACs is anticipated to reverse all HIV-1 Nef functions, thereby restoring immune responses against HIV-1 reservoir cells.

Applications

• Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS)
• HIV-associated neurodegenerative disorders, cardiovascular complications and cancers

Advantages

While existing antiretroviral drugs can manage HIV as a chronic condition, long-term drug treatment causes metabolic disturbances, organ damage, and promotes drug resistance. Therefore, there is an urgent need to find treatments that not only suppress HIV replication but also provide a path to eradication of HIV-infected cells through clearance of latent viral reservoirs.

Our PROTAC molecules selectively target HIV Nef, for which there are currently no FDA-approved drugs. Prior work has shown that individuals infected with Nef-defective HIV have negligible viral loads and do not progress to AIDS even in the absence of standard antiretroviral therapy. This observation supports the idea that targeted degradation of Nef will not only suppress viral replication but also induce the anti-HIV immune response to clear viral reservoirs.

IP Status

https://patents.google.com/patent/WO2024263781A1

Related Publication(s)

Emert-Sedlak, L. A., Tice, C. M., Shi, H., Alvarado, J. J., Shu, S. T., Reitz, A. B., & Smithgall, T. E. (2024). PROTAC-mediated degradation of HIV-1 Nef efficiently restores cell-surface CD4 and MHC-I expression and blocks HIV-1 replication. Cell Chemical Biology, 31(4), 658-668.e14. https://doi.org/10.1016/j.chembiol.2024.02.004

Emert-Sedlak, L. A., Shi, H., Tice, C. M., Chen, L., Alvarado, J. J., Shu, S. T., Du, S., Thomas, C. E., Wrobel, J. E., Reitz, A. B., & Smithgall, T. E. (2022). Antiretroviral Drug Discovery Targeting the HIV-1 Nef Virulence Factor. Viruses, 14(9), 2025. https://doi.org/10.3390/v14092025

Shi, H., Tice, C. M., Emert-Sedlak, L., Chen, L., Li, W. F., Carlsen, M., Wrobel, J. E., Reitz, A. B., & Smithgall, T. E. (2019). Tight-Binding Hydroxypyrazole HIV-1 Nef Inhibitors Suppress Viral Replication in Donor Mononuclear Cells and Reverse Nef-Mediated MHC-I Downregulation. ACS Infectious Diseases, 6(2), 302–312. https://doi.org/10.1021/acsinfecdis.9b00382