%0 Journal Article
%T Protease-Mediated Maturation of HIV: Inhibitors of Protease and the Maturation Process
%A Catherine S. Adamson
%J Molecular Biology International
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/604261
%X 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. 1. Introduction Human Immunodeficiency Virus Type 1 (HIV-1) is the causative agent of the worldwide Acquired Immunodeficiency Syndrome (AIDS) epidemic. Approximately 34 million people were estimated to be living with HIV at the end of 2010. The number of people infected is a consequence of continued large numbers of new HIV-1 infections together with a reduction in AIDS-related deaths due to a significant expansion in access to antiretroviral drug therapy [1]. In the absence of an effective vaccine or cure, antiviral drugs are currently the only treatment option available to HIV-infected patients. Therapeutic regimes commonly termed HAART (highly active antiretroviral therapy) suppress viral replication but do not eradicate the virus; therefore, treatment must be administered on a lifelong basis [2, 3]. HAART consists of the simultaneous use of a combination of three or four different antiretroviral drugs. This combinational approach is required due to the ease with which HIV-1 can acquire drug resistance to a single drug administered as monotherapy [3, 4]. Drug resistance arises due to the high degree of HIV-1 genetic diversity within the virus population (quasi-species) infecting an individual patient. This genetic
%U http://www.hindawi.com/journals/mbi/2012/604261/