2ND LOCUS INVOLVED IN HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 RESISTANCE TO PROTEASE INHIBITORS

Protease inhibitors are potent antiviral agents against human immunode ficiency virus type 1, As with reverse transcriptase inhibitors, howev er, resistance to protease inhibitors can develop and is attributed to the appearance of mutations in the protease gene. With the substrate analog protease inhibitors BILA 1906 BS and BILA 2185 BS, 350- to 1,50 0-fold-resistant variants have been selected in vitro and were found n ot only to contain mutations in the protease gene but also to contain mutations in Gag precursor p1/p6 and/or NC (p7)/pl cleavage sites, Mut ations in cleavage sites give rise to better peptide substrates for th e protease in vitro and to improved processing of p15 precursors in dr ug-resistant clones, Importantly, removal of cleavage site mutations i n resistant clones leads to a decrease or even an absence of viral gro wth, confirming their role in viral fitness, Therefore, these second-l ocus mutations indicate that cleavage of p15 is a rate-limiting step i n polyprotein processing in highly resistant viruses, The functional c onstraint of p15 processing also suggests that additional selective pr essure could further compromise viral fitness and maintain the benefit s of antiviral therapies.