The p2 domain of human immunodeficiency virus type 1 Gag regulates sequential proteolytic processing and is required to produce fully infectious virions
Open accessAbstract
The proteolytic processing sites of the human immunodeficiency virus type 1 (HIV-1) Gag precursor are cleaved in a sequential manner by the viral protease. We investigated the factors that regulate sequential processing. When full-length Gag protein was digested with recombinant HIV-1 protease in vitro, four of the five major processing sites in Gag were cleaved at rates that differ by as much as 400-fold. Three of these four processing sites were cleaved independently of the others. The CA/p2 site, however, was cleaved approximately 20-fold faster when the adjacent downstream p2/NC site was blocked from cleavage or when the p2 domain of Gag was deleted. These results suggest that the presence of a C-terminal p2 tail on processing intermediates slows cleavage at the upstream CA/p2 site. We also found that lower pH selectively accelerated cleavage of the CA/p2 processing site in the full-length precursor and as a peptide primarily by a sequence-based mechanism rather than by a change in protein conformation. Deletion of the p2 domain of Gag results in released virions that are less infectious despite the presence of the processed final products of Gag. These findings suggest that the p2 domain of HIV-1 Gag regulates the rate of cleavage at the CA/p2 processing site during sequential processing in vitro and in infected cells and that p2 may function in the proper assembly of virions.
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Tight control of proteolytic cleavages at different sites is required for successful maturation.
“Tight control of proteolytic cleavages at different sites is required for successful maturation, and the process is a major target of antiretroviral drugs.”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [63]
Once the protease is activated, the rate of cleavage differs between each cleavage site in Gag.
“Once the protease is activated, the rate of cleavage differs between each cleavage site in Gag.”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [63]
The differing cleavage rates determine a kinetically regulated, ordered release of the different Gag domains.
“This determines a kinetically regulated, ordered release of the different domains”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [63]
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- Authors
- Pettit, S. C., Moody, M. D., Wehbie, R. S., Kaplan, A. H., Nantermet, P. V., Klein, C. A., & Swanstrom, R.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 1994-12
- Volume
- 68
- Issue
- 12
- Pages
- 8017-8027
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC237265
- OpenAlex
- W1595806441
- Cited by
- 355
- References
- 3
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 3 · 2022: 10 · 2021: 13 · 2020: 9 · 2019: 9 · 2018: 8 · 2017: 12 · 2016: 12 · 2015: 24 · 2014: 12 · 2013: 20 · 2012: 15
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ai025321-13, 1f32ai008400-01a1, 5f32ai008767-02)
- National Institute of Allergy and Infectious Diseases (F32-AI08400, R01 AI 25321, F32-AI08767)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Keywords
- HIV-1 Gag, P2 domain, HIV-1 protease, cleavage kinetics, pH-dependent cleavage, viral assembly, infectious virion production
- MeSH terms
- Amino Acid Sequence, Base Sequence, Cloning, Molecular, HeLa Cells, Humans, Kinetics, Molecular Sequence Data, Oligodeoxyribonucleotides, Protein Precursors, Protein Processing, Post-Translational, Recombinant Proteins, RNA, Messenger, Transfection, Protein Biosynthesis, Virion, Blotting, Western, HIV-1, Gene Products, gag, Genes, gag, Mutagenesis, Site-Directed
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