Journal
ANTIVIRAL RESEARCH
Volume 85, Issue 1, Pages 59-74Publisher
ELSEVIER
DOI: 10.1016/j.antiviral.2009.10.003
Keywords
HIV; Protease; Inhibitor; Drug resistance; Therapy
Categories
Funding
- EU [LSHP-CT-2007-037693]
- Dutch AIDSfonds [2006028]
- Netherlands Organization for Scientific Research (NWO) VIDI [91796349]
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HIV protease plays a crucial role in the viral life cycle and is essential for the generation of mature infectious virus particles. Detailed knowledge of the structure of HIV protease and its substrate has led to the design of specific HIV protease inhibitors. Unfortunately, resistance to all protease inhibitors (Pis) has been observed and the genetic basis of resistance has been well documented over the past 15 years. The arrival of the early Pis was a pivotal moment in the development of antiretroviral therapy. They made possible the dual class triple combination therapy that became known as HAART. However, the clinical utility of the first generation of Pis was limited by low bioavailability and high pill burdens, which ultimately reduced adherence and limited long-term viral inhibition. When therapy failure occurred multiple protease resistance mutations were observed, often resulting in broad class resistance. To combat PI-resistance development, second-generation approaches have been developed. The first advance was to increase the level of existing Pis in the plasma by boosting with ritonavir. The second was to develop novel Pis with high potency against the known PI-resistant HIV protease variants. Both approaches increased the number of protease mutations required for clinical resistance, thereby raising the genetic barrier. This review provides an overview of the history of protease inhibitor therapy, its current status and future perspectives. It forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010. (C) 2009 Elsevier B.V. All rights reserved.
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