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A Restriction Enzyme Based Cloning Method to Assess the In vitro Replication Capacity of HIV-1 Subtype C Gag-MJ4 Chimeric Viruses
Published on: August 31, 2014
HIV-1 Gag processing intermediates trans-dominantly interfere with HIV-1 infectivity
Barbara Müller1, Maria Anders, Hisashi Akiyama
1Department of Virology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany. barbara_mueller@med.uni-heidelberg.de
The Journal of Biological Chemistry
|August 12, 2009
Summary
Low protease inhibitor concentrations impair human immunodeficiency virus (HIV) polyprotein processing, reducing particle infectivity. Partially processed Gag intermediates can dominantly affect HIV maturation, highlighting the CA-SP1 cleavage site
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Protease inhibitors (PI) are crucial for human immunodeficiency virus (HIV) treatment by blocking viral polyprotein processing.
- A direct quantitative link between Gag processing impairment and virion infectivity at low PI concentrations is not well understood.
Purpose of the Study:
- To investigate the consequences of partial polyprotein processing on HIV particle infectivity.
- To analyze the impact of partially processed Gag forms on wild-type HIV maturation and replication.
Main Methods:
- Producing HIV particles with limiting PI concentrations.
- Co-transfecting wild-type proviral plasmids with Gag cleavage site mutants.
- Analyzing viral entry, reverse transcriptase activity, and post-reverse transcription replication steps.
Main Results:
- Low PI concentrations induced subtle Gag processing changes, significantly reducing particle infectivity.
- Partially processed Gag intermediates exhibited a trans-dominant effect on wild-type HIV maturation.
- The CA-SP1 cleavage site was critical for this trans-dominant effect and Gag processing.
Conclusions:
- Low levels (<5%) of Gag processing intermediates can dominantly inhibit HIV particle maturation.
- The CA-SP1 cleavage is particularly important for HIV maturation.
- These findings may explain PI efficacy in vivo and inform antiviral drug mechanisms, including bevirimat.
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