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Structure, function, and inhibitor targeting of HIV-1 Nef-effector kinase complexes
Ryan P Staudt1, John J Alvarado1, Lori A Emert-Sedlak1
1Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
The Journal of Biological Chemistry
|August 31, 2020
Summary
New antiretroviral therapies targeting the HIV-1 Nef protein show promise for clearing the virus. Inhibiting Nef
Area of Science:
- Virology and Immunology
- Drug Discovery and Development
Background:
- Antiretroviral therapy (ART) manages Human Immunodeficiency Virus (HIV) but does not eradicate it, necessitating lifelong treatment.
- Drug resistance and limited vaccine options underscore the need for novel strategies to clear HIV.
- The HIV-1 accessory protein Nef is crucial for viral pathogenesis, replication, and immune evasion, making it a key therapeutic target.
Purpose of the Study:
- To review the structure, function, and biological significance of Nef's interactions with host cell protein-tyrosine kinases.
- To explore the potential of targeting Nef-mediated kinase activation for developing new antiretroviral drugs.
- To assess the efficacy of Nef inhibitors in restoring immune responses against HIV-infected cells and latent reservoirs.
Main Methods:
- Review of existing literature on HIV-1 Nef protein structure, function, and interactions with host cell proteins, particularly protein-tyrosine kinases.
- Analysis of drug discovery efforts targeting Nef-mediated kinase activation and Nef-induced MHC-I down-regulation.
- Evaluation of *in vitro* studies demonstrating the impact of Nef inhibitors on immune responses and viral clearance strategies.
Main Results:
- Nef enhances HIV replication and immune escape by interacting with host cell proteins, notably protein-tyrosine kinases involved in signaling and trafficking.
- Drug discovery targeting Nef has identified inhibitors effective against multiple Nef functions.
- Pharmacological inhibition of Nef-induced MHC-I down-regulation restores adaptive immune responses against HIV-infected cells *in vitro*.
Conclusions:
- Targeting the HIV-1 Nef protein offers a promising strategy for developing novel antiretroviral therapies.
- Inhibitors of Nef-mediated kinase activation and MHC-I down-regulation can restore immune surveillance of HIV-infected cells.
- These approaches hold potential for enhancing immune recognition of latent viral reservoirs, contributing to HIV clearance.
Keywords:
AIDSBtkCD4HIV-1 NefHckItkMHC-ISH2 domainSH3 domainSrc homology 2 domain (SH2 domain)Src homology 3 domain (SH3 domain)Src-family kinasesTec-family kinasesbimolecular fluorescence complementation (BiFC)dimerizationendocytosishuman immunodeficiency virus (HIV)infectious diseasemajor histocompatibility complex (MHC)protein-protein interactionMore Related Videos
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