The capsid-spacer peptide 1 Gag processing intermediate is a dominant-negative inhibitor of HIV-1 maturation.
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.
Checkley
Mary Ann
MA
Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute-Frederick, Bldg. 535/Rm 108, 1050 Boyles Street, Frederick, MD 21702-1201, USA.
Luttge
Benjamin G
BG
Soheilian
Ferri
F
Nagashima
Kunio
K
Freed
Eric O
EO
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology; D036022:Capsid Proteins / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D009154:Mutation; D011499:Protein Processing, Post-Translational; D013386:Succinates / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology; D019065:Virus Assembly; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000502:physiology; D053978:Pentacyclic Triterpenes
D019380:Anti-HIV Agents; D036022:Capsid Proteins; D013386:Succinates; D014315:Triterpenes; D054301:gag Gene Products, Human Immunodeficiency Virus; C479935:bevirimat; D053978:Pentacyclic Triterpenes