Mechanism and Kinetics of HIV-1 Protease Activation

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2025 Jan 8

PMID 39772135

Authors

Caroline O Tabler

John C Tilton

Affiliations

Soon will be listed here.

Abstract

The HIV-1 protease is a critical enzyme for viral replication. Because protease activity is necessary to generate mature infectious virions, it is a primary target of antiretroviral treatment. Here, we provide an overview of the mechanisms regulating protease activation and the methods available to assess protease activity. Finally, we will highlight some of the key discoveries regarding the kinetics of protease activation from the last decade, including how the manipulation of activation kinetics may provide novel HIV-1 treatment strategies.

References

Rheinemann L, Downhour D, Bredbenner K, Mercenne G, Davenport K, Schmitt P . RetroCHMP3 blocks budding of enveloped viruses without blocking cytokinesis. Cell. 2021; 184(21):5419-5431.e16. PMC: 8929533. DOI: 10.1016/j.cell.2021.09.008. View

Lin Z, Cantone J, Lu H, Nowicka-Sans B, Protack T, Yuan T . Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors. PLoS Pathog. 2016; 12(11):e1005990. PMC: 5125710. DOI: 10.1371/journal.ppat.1005990. View

Centazzo M, Manganaro L, Alvisi G . Cellular Targets of HIV-1 Protease: Just the Tip of the Iceberg?. Viruses. 2023; 15(3). PMC: 10053624. DOI: 10.3390/v15030712. View

Gaber R, Majerle A, Jerala R, Bencina M . Noninvasive high-throughput single-cell analysis of HIV protease activity using ratiometric flow cytometry. Sensors (Basel). 2013; 13(12):16330-46. PMC: 3892856. DOI: 10.3390/s131216330. View

Yu F, Chou T, Liao W, Huang K, Wang C . Gag-Pol Transframe Domain p6* Is Essential for HIV-1 Protease-Mediated Virus Maturation. PLoS One. 2015; 10(6):e0127974. PMC: 4451514. DOI: 10.1371/journal.pone.0127974. View

Sood C, Francis A, Desai T, Melikyan G . An improved labeling strategy enables automated detection of single-virus fusion and assessment of HIV-1 protease activity in single virions. J Biol Chem. 2017; 292(49):20196-20207. PMC: 5724006. DOI: 10.1074/jbc.M117.818088. View

Tabler C, Wegman S, Chen J, Shroff H, Alhusaini N, Tilton J . The HIV-1 Viral Protease Is Activated during Assembly and Budding Prior to Particle Release. J Virol. 2022; 96(9):e0219821. PMC: 9093094. DOI: 10.1128/jvi.02198-21. View

Lee Y, Tian C, Yu X . A bipartite membrane-binding signal in the human immunodeficiency virus type 1 matrix protein is required for the proteolytic processing of Gag precursors in a cell type-dependent manner. J Virol. 1998; 72(11):9061-8. PMC: 110323. DOI: 10.1128/JVI.72.11.9061-9068.1998. View

Dorfman T, Mammano F, Haseltine W, Gottlinger H . Role of the matrix protein in the virion association of the human immunodeficiency virus type 1 envelope glycoprotein. J Virol. 1994; 68(3):1689-96. PMC: 236628. DOI: 10.1128/JVI.68.3.1689-1696.1994. View

10.

Shu X, Leiderman P, Gepshtein R, Smith N, Kallio K, Huppert D . An alternative excited-state proton transfer pathway in green fluorescent protein variant S205V. Protein Sci. 2007; 16(12):2703-10. PMC: 2222808. DOI: 10.1110/ps.073112007. View

11.

Vestad B, Llorente A, Neurauter A, Phuyal S, Kierulf B, Kierulf P . Size and concentration analyses of extracellular vesicles by nanoparticle tracking analysis: a variation study. J Extracell Vesicles. 2017; 6(1):1344087. PMC: 5533132. DOI: 10.1080/20013078.2017.1344087. View

12.

Mattei S, Anders M, Konvalinka J, Krausslich H, Briggs J, Muller B . Induced maturation of human immunodeficiency virus. J Virol. 2014; 88(23):13722-31. PMC: 4248963. DOI: 10.1128/JVI.02271-14. View

13.

Huang M, Orenstein J, Martin M, Freed E . p6Gag is required for particle production from full-length human immunodeficiency virus type 1 molecular clones expressing protease. J Virol. 1995; 69(11):6810-8. PMC: 189593. DOI: 10.1128/JVI.69.11.6810-6818.1995. View

14.

Schimer J, Pavova M, Anders M, Pachl P, Sacha P, Cigler P . Triggering HIV polyprotein processing by light using rapid photodegradation of a tight-binding protease inhibitor. Nat Commun. 2015; 6:6461. PMC: 4366505. DOI: 10.1038/ncomms7461. View

15.

Garrus J, von Schwedler U, Pornillos O, Morham S, Zavitz K, Wang H . Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell. 2001; 107(1):55-65. DOI: 10.1016/s0092-8674(01)00506-2. View

16.

Takagi S, Momose F, Morikawa Y . FRET analysis of HIV-1 Gag and GagPol interactions. FEBS Open Bio. 2017; 7(11):1815-1825. PMC: 5666392. DOI: 10.1002/2211-5463.12328. View

17.

Bonar M, Tabler C, Haqqani A, Lapointe L, Galiatsos J, Joussef-Pina S . Nanoscale flow cytometry reveals interpatient variability in HIV protease activity that correlates with viral infectivity and identifies drug-resistant viruses. Sci Rep. 2020; 10(1):18101. PMC: 7583244. DOI: 10.1038/s41598-020-75118-1. View

18.

Wlodawer A, Miller M, Jaskolski M, Sathyanarayana B, Baldwin E, Weber I . Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science. 1989; 245(4918):616-21. DOI: 10.1126/science.2548279. View

19.

Neefjes J, Dantuma N . Fluorescent probes for proteolysis: tools for drug discovery. Nat Rev Drug Discov. 2004; 3(1):58-69. PMC: 7097193. DOI: 10.1038/nrd1282. View

20.

Freed E, Martin M . Domains of the human immunodeficiency virus type 1 matrix and gp41 cytoplasmic tail required for envelope incorporation into virions. J Virol. 1996; 70(1):341-51. PMC: 189823. DOI: 10.1128/JVI.70.1.341-351.1996. View