The Capsid-spacer Peptide 1 Gag Processing Intermediate is a Dominant-negative Inhibitor of HIV-1 Maturation

Overview

Journal Virology

Specialty Microbiology

Date 2010 Feb 23

PMID 20172577

Citations 43

Authors

Mary Ann Checkley

Benjamin G Luttge

Ferri Soheilian

Kunio Nagashima

Eric O Freed

Affiliations

Soon will be listed here.

Abstract

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.

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