
<ArticleTitle>Resistance to nucleoside analog reverse transcriptase inhibitors mediated by human immunodeficiency virus type 1 <prot>p6 protein</prot>.</ArticleTitle>
<AbstractText>Resistance of human immunodeficiency virus type 1 (HIV-1) to antiretroviral agents results from target gene mutation within the <prot>pol</prot> gene, which encodes the viral protease, <prot>reverse transcriptase</prot> (<prot>RT</prot>), and <prot>integrase</prot>. We speculated that mutations in genes other that the drug target could lead to drug resistance. For this purpose, the <prot>p1</prot>-<prot>p6</prot>(<prot>gag</prot>)-<prot>p6</prot>(<prot>pol</prot>) region of HIV-1, placed immediately upstream of <prot>pol</prot>, was analyzed. This region has the potential to alter <prot>Pol</prot> through frameshift regulation (<prot>p1</prot>), through improved packaging of viral enzymes (<prot>p6</prot>(<prot>Gag</prot>)), or by changes in activation of the viral protease (<prot>p6</prot>(<prot>Pol</prot>)). Duplication of the proline-rich <prot>p6</prot>(<prot>Gag</prot>) PTAP motif, necessary for late viral cycle activities, was identified in plasma virus from 47 of 222 (21.2%) patients treated with nucleoside analog <prot>RT</prot> inhibitor (NRTI) antiretroviral therapy but was identified very rarely from drug-naïve individuals. Molecular clones carrying a 3-amino-acid duplication, APPAPP (transframe duplication SPTSPT in <prot>p6</prot>(<prot>Pol</prot>)), displayed a delay in protein maturation; however, they packaged a 34% excess of <prot>RT</prot> and exhibited a marked competitive growth advantage in the presence of NRTIs. This phenotype is reminiscent of the inoculum effect described in bacteriology, where a larger input, or a greater infectivity of an organism with a wild-type antimicrobial target, leads to escape from drug pressure and a higher MIC in vitro. Though the mechanism by which the PTAP region participates in viral maturation is not known, duplication of this proline-rich motif could improve assembly and packaging at membrane locations, resulting in the observed phenotype of increased infectivity and drug resistance.</AbstractText>
