Role of Gag in HIV Resistance to Protease Inhibitors 英文参考文献.docVIP

Viruses 2010, 2, 1411-1426; doi:10.3390/v2071411 OPEN ACCESS viruses ISSN 1999-4915 /journal/viruses Review Role of Gag in HIV Resistance to Protease Inhibitors Fran?ois Clavel 1,2,3,* and Fabrizio Mammano 4,5 1 Inserm U941, Paris 75010, France 2 Institut Universitaire d’Hématologie, Université Paris Diderot, Paris 75010, France 3 H?pital Saint Louis, AP-HP, Paris 75010, France 4 Institut Pasteur, Unité Virus et Immunité, Paris 75015, France 5 CNRS URA 3015, Paris 75015, France * Author to whom correspondence should be addressed; E-Mail: francois.clavel@inserm.fr; Tel.: +331-5727-6764; Fax: +331-5727-6804. Received: 7 April 2010; in revised form: 21 June 2010 / Accepted: 25 June 2010 / Published: 5 July 2010 Abstract: Cleavage of Gag and Gag-Pol precursors by the viral protease is an essential step in the replication cycle of HIV. Protease inhibitors, which compete with natural cleavage sites, strongly impair viral infectivity and have proven to be highly valuable in the treatment of HIV-infected subjects. However, as with all other antiretroviral drugs, the clinical benefit of protease inhibitors can be compromised by resistance. One key feature of HIV resistance to protease inhibitors is that the mutations that promote resistance are not only located in the protease itself, but also in some of its natural substrates. The best documented resistance-associated substrate mutations are located in, or near, the cleavage sites in the NC/SP2/p6 region of Gag. These mutations improve interactions between the substrate and the mutated enzyme and correspondingly increase cleavage. Initially described as compensatory mutations able to partially correct the loss of viral fitness that results from protease mutations, changes in Gag are now recognized as being directly involved in resistance. Besides NC/SP2/p6 mutations, polymorphisms in other regions of Gag have been found to exert variou