Journal
VIROLOGY
Volume 400, Issue 1, Pages 137-144Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2010.01.028
Keywords
HIV-1; Gag; Virus maturation; Assembly; Retrovirus; Protease
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Funding
- Center for Cancer Research, National Cancer Institute, NIH [N01-CO-12400]
- Intramural AIDS Targeted Antiviral Program
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The human immunodeficiency virus type 1 (HIV-1) maturation inhibitor bevirimat disrupts virus replication by inhibiting the cleavage of the capsid-spacer peptide 1 (CA-SP1) Gag processing intermediate to mature CA. The observation that bevirimat delays but does not completely block CA-SP1 processing suggests that the presence of uncleaved CA-SP1 may disrupt the maturation process in trans. In this study, we validate this hypothesis by using a genetic approach to demonstrate that a non-cleavable CA-SP1 Mutant exerts a dominant-negative effect on Maturation of wild-type HIV-1. In contrast, a mutant in which cleavage can occur internally within SP1 is significantly less potent as a dominant-negative inhibitor. We also show that bevirimat blocks processing at both the major CA-SP1 cleavage site and the internal site. These data underscore the importance of full CA-SP1 processing for HIV-1 maturation and highlight the therapeutic potential of inhibitors that target this Gag cleavage event. Published by Elsevier Inc.
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