ArticleProceedings of the National Academy of Sciences of the United States of America1995
Trans-dominant inhibitory human immunodeficiency virus type 1 protease monomers prevent protease activation and virion maturation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1995. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 60 citations in OpenAlex.
- Structures of Substrate Complexes of Foamy Viral Protease-Reverse Transcriptase.Journal of virology · 2021Article
- Inhibitory Effects of HIV-2 Vpx on Replication of HIV-1.Journal of virology · 2018Article
- Rationale and clinical utility of the darunavir-cobicistat combination in the treatment of HIV/AIDS.Drug design, development and therapy · 2015Review
- HIV-1 matrix domain removal ameliorates virus assembly and processing defects incurred by positive nucleocapsid charge elimination.FEBS open bio · 2015Article
- Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Tsg101 regulates PI(4,5)P2/Ca(2+) signaling for HIV-1 Gag assembly.Frontiers in microbiology · 2014Article
- Sprouty2 regulates PI(4,5)P2/Ca2+ signaling and HIV-1 Gag release.Journal of molecular biology · 2011Article
- Novel macromolecular inhibitors of human immunodeficiency virus-1 protease.Protein engineering, design & selection : PEDS · 2008Article
- Effect of the active site D25N mutation on the structure, stability, and ligand binding of the mature HIV-1 protease.The Journal of biological chemistry · 2008Article
- Targeting human immunodeficiency virus type 1 assembly, maturation and budding.Drug target insights · 2007Article
- HIV protease-activated molecular switches based on beta-glucuronidase and alkaline phosphatase.Combinatorial chemistry & high throughput screening · 2006Article
- Virion instability of human immunodeficiency virus type 1 reverse transcriptase (RT) mutated in the protease cleavage site between RT p51 and the RT RNase H domain.Journal of virology · 2005Article
- Herpesvirus protease inhibition by dimer disruption.Journal of virology · 2004Article
- HIV-1 proprotein processing as a target for gene therapy.Gene therapy · 2003Article
- Altered substrate specificity of drug-resistant human immunodeficiency virus type 1 protease.Journal of virology · 2002Article
- Maintenance of the Gag/Gag-Pol ratio is important for human immunodeficiency virus type 1 RNA dimerization and viral infectivity.Journal of virology · 2001Article
- Genetic selection for dissociative inhibitors of designated protein-protein interactions.Nature biotechnology · 2000Article
- Inhibition of HIV/SIV replication by dominant negative Gag mutants.Virus genes · 1999Article
- Importance of ribosomal frameshifting for human immunodeficiency virus type 1 particle assembly and replication.Journal of virology · 1998Article
- Intracellular expression of human immunodeficiency virus type 1 (HIV-1) protease variants inhibits replication of wild-type and protease inhibitor-resistant HIV-1 strains in human T-cell lines.Journal of virology · 1996Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Production of infectious human immunodeficiency virus (HIV) requires proper polyprotein processing by the dimeric viral protease. The trans-dominant inhibitory activity of a defective protease monomer with the active site Asp-25 changed to Asn was measured by transient transfection. A proviral plasmid that included the drug-selectable Escherichia coli gpt gene was used to deliver the wild-type (wt) or mutant proteases to cultured cells. Coexpression of the wt proviral DNA (HIV-gpt) with increasing amounts of the mutant proviral DNA (HIV-gpt D25N) results in a concomitant decrease in proteolytic activity monitored by in vivo viral polyprotein processing. The viral particles resulting from inactivation of the protease were mostly immature, consisting predominantly of unprocessed p55gag and p160gag-pol polyproteins. In the presence of HIV-1 gp160 env, the number of secreted noninfectious particles correlated with the presence of increasing amounts of the defective protease. Greater than 97% reduction in infectivity was observed at a 1:6 ratio of wt to defective protease DNA. This provides an estimate of the level of inhibition required for effectively preventing virion processing. Stable expression of the defective protease in monkey cells reduced the yield of infectious particles from these cells by 90% upon transfection with the wt proviral DNA. These results show that defective subunits of the viral protease exert a trans-dominant inhibitory effect resulting from the formation of catalytically compromised heterodimers in vivo, ultimately yielding noninfectious viral particles.
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