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Molecular Biology International
Volume 2012 (2012), Article ID 604261, 13 pages
http://dx.doi.org/10.1155/2012/604261
Review Article

Protease-Mediated Maturation of HIV: Inhibitors of Protease and the Maturation Process

Biomedical Sciences Research Complex, School of Medicine, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, UK

Received 19 March 2012; Accepted 30 May 2012

Academic Editor: Abdul Waheed

Copyright © 2012 Catherine S. Adamson. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Protease-mediated maturation of HIV-1 virus particles is essential for virus infectivity. Maturation occurs concomitant with immature virus particle release and is mediated by the viral protease (PR), which sequentially cleaves the Gag and Gag-Pol polyproteins into mature protein domains. Maturation triggers a second assembly event that generates a condensed conical capsid core. The capsid core organizes the viral RNA genome and viral proteins to facilitate viral replication in the next round of infection. The fundamental role of proteolytic maturation in the generation of mature infectious particles has made it an attractive target for therapeutic intervention. Development of small molecules that target the PR active site has been highly successful and nine protease inhibitors (PIs) have been approved for clinical use. This paper provides an overview of their development and clinical use together with a discussion of problems associated with drug resistance. The second-half of the paper discusses a novel class of antiretroviral drug termed maturation inhibitors, which target cleavage sites in Gag not PR itself. The paper focuses on bevirimat (BVM) the first-in-class maturation inhibitor: its mechanism of action and the implications of naturally occurring polymorphisms that confer reduced susceptibility to BVM in phase II clinical trials.