HIV-1 Envelope Clinical Isolates from Vicriviroc Resistant Subjects. Human immunodeficiency virus 1
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The HIV-1 envelope interacts with coreceptors CCR5 and CXCR4 in a dynamic, multi-step process, its molecular details not clearly delineated. Clinical application of CCR5 antagonists often results in tropism shift and subsequent therapeutic failure. Here we describe a novel experimental approach using full-length patient-derived gp160 quasispecies libraries cloned into HIV-1 molecular clones, separation of these quasispecies based on their phenotypic tropism in vitro, and deep sequence of the resultant functional variants by Illumina HiSeq and Pacific Biosciences for structure-function analyses. Through in-depth analysis of functionally validated envelope sequences from patients who failed CCR5 antagonist therapy, we revealed determinants strongly associated with coreceptor specificity.
