role of gag in hiv resistance to protease inhibitors呕吐在艾滋病毒抗蛋白酶抑制剂.pdfVIP

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 François 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 Hôpital 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. The