Active human immunodeficiency virus protease is required for viral infectivity
Open accessAbstract
Retroviral proteins are synthesized as polyprotein precursors that undergo proteolytic cleavages to yield the mature viral proteins. The role of the human immunodeficiency virus (HIV) protease in the viral replication cycle was examined by use of a site-directed mutation in the protease gene. The HIV protease gene product was expressed in Escherichia coli and observed to cleave HIV gag p55 to gag p24 and gag p17 in vitro. Substitution of aspartic acid residue 25 (Asp-25) of this protein with an asparagine residue did not affect the expression of the protein, but it eliminated detectable in vitro proteolytic activity against HIV gag p55. A mutant HIV provirus was constructed that contained the Asn-25 mutation within the protease gene. SW480 human colon carcinoma cells transfected with the Asn-25 mutant proviral DNA produced virions that contained gag p55 but not gag p24, whereas virions from cells transfected with the wild-type DNA contained both gag p55 and gag p24. The mutant virions were not able to infect MT-4 lymphoid cells. In contrast, these cells were highly sensitive to infection by the wild-type virions. These results demonstrate that the HIV protease is an essential viral enzyme and, consequently, an attractive target for anti-HIV drugs.
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Gag is critical for the encapsidation of gRNA into the assembling virus particles, with the NC domain being the most relevant for RNA packaging.
“Gag is critical for the encapsidation of gRNA into the assembling virus particles, with the NC domain being the most relevant for RNA packaging”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Kohl et al. 1988
Mutations in the PR coding domain or inhibition of PR activity result in virions containing unprocessed Gag, rendering them noninfectious.
“mutations in the PR coding domain or inhibition of PR activity result in virions containing unprocessed Gag, rendering them noninfectious”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Kohl et al. 1988
Improper cleavage by the PR results in defective, noninfectious retroviral particles.
“Improper cleavage by the PR results in defective, noninfectious retroviral particles”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Kohl et al. 1988
Cites
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Inhibitors of Strand Transfer That Prevent Integration and Inhibit HIV-1 Replication in Cells
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Complete mutagenesis of the HIV-1 protease
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Retroviral proteases and their roles in virion maturation
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A systematic method for identifying small-molecule modulators of protein–protein interactions
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Current State of Therapeutics for HTLV-1
Wang, T. T., Hirons, A., Doerflinger, M., Morris, K. V., Ledger, S., Purcell, D. F. J., Kelleher, A. D., & Ahlenstiel, C. L. (2024) · Viruses · doi:10.3390/v16101616 · Cited by 22 · see citing works
“Integrase; DNA provirus integration [30] Virion [33] here are also two regulatory proteins, Tax and Rex, which are trans-activators of transcription, the inhibition of which by the HTLV-1 p30II viral protein inhibits virus expression and suppresses Tax/HBZ-induced oxidative and metabolic toxicity…”
BackgroundBeyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication
Jehad, M. A., Ali, L. M., Pillai, V. N., Prabhu, S. G., Mustafa, F., & Rizvi, T. A. (2026) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuaf066 · Cited by 5 · see citing works
“…PR coding domain or inhibition of PR activity result in virions containing unprocessed Gag, rendering them noninfectious (Craw-ford and Goff 1985 , Katoh et al. 1985 , Kohl et al. 1988 , Ashorn et al. 1990 , Meek et al. 1990 , Roberts et al. 1990 , Stewart et al. 1990 , Sommerfelt et al. 1992 ).”
- Authors
- Kohl, N. E., Emini, E. A., Schleif, W. A., Davis, L. J., Heimbach, J. C., Dixon, R. A., Scolnick, E. M., & Sigal, I. S.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1988-07
- Volume
- 85
- Issue
- 13
- Pages
- 4686-4690
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC280500
- OpenAlex
- W1974224443
- Cited by
- 1,307
- References
- 1
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 21 · 2023: 10 · 2022: 20 · 2021: 11 · 2020: 22 · 2019: 18 · 2018: 18 · 2017: 16 · 2016: 18 · 2015: 36 · 2014: 31 · 2013: 32 · 2012: 42
- FWCI
- 13.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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 protease, viral infectivity, Gag p24, site-directed mutations, viral life cycle, anti-HIV drug targets, site-directed mutagenesis
- MeSH terms
- Asparagine, Binding Sites, HIV, Endopeptidases, Protein Precursors, Proviruses, Recombinant Fusion Proteins, Retroviridae Proteins, Viral Proteins, Virulence, Virus Replication, Gene Products, gag, HIV Protease
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